Hair growth composition and method

ABSTRACT

The present invention relates to compositions for and methods of retarding hair loss or facilitating hair growth comprising a hair growth active, a mixture of C 12 -C 15  alkyl lactates and a viscosity modifying agent comprising at least one cellulose and/or a cellulose derivative. Clear compositions are also disclosed.

FIELD OF THE INVENTION

The present invention relates to compositions for and methods ofretarding hair loss or facilitating hair growth comprising a hair growthactive, a mixture of C₁₂-C₁₅ alkyl lactates and a viscosity modifyingagent comprising at least one cellulose and/or a cellulose derivative.Clear compositions are also disclosed.

BACKGROUND OF THE INVENTION

Alopecia, or hair loss, in its various forms is an ongoing problemafflicting mankind and animals. Men, woman and children can all sufferfrom alopecia, which can be result of one, or a combination of, factorsincluding genetic factors, hormonal factors, surgery, trauma,chemotherapy, aging, certain drug side effects and stress. Theuniversality of the occurrence of alopecia has led to continuing effortsthroughout history to discover compositions for stimulating hair growthand preventing hair loss.

A number of “natural” remedies for alopecia based solely on herbs andplant extracts have been proposed. However, such compounds have provenclinically to have very little if any effect.

Accordingly, an aspect of the present invention is to provide a methodfor reducing hair loss and facilitate hair growth and/or providing athicker, denser or richer hair coat.

Another aspect of the present disclosure is concerned with methods ofusing compositions comprising at least one hair growth stimulator, andat least one C₈-C₂₄ alcohol ester of a carboxylic acid.

Another aspect of the present invention is improving the temperaturestability of solution or gel compositions containing from about 0.1% toabout 20% by weight of a hair growth or hair regrowth compound (such asminoxidil or pharmaceutically acceptable addition salts thereof); fromabout 0.5% to about 10% by weight of an oil phase or oily compound; fromabout 0% to about 60% of a dihydric alcohol (such as propylene glycol);and from about 0 to about 65% by weight of a C₂-C₄ alcohol (such asethanol).

Another aspect of the present invention is providing clear (or reducedturbidity or cloudiness) solution or gel compositions of pH less than 5containing from about 0.1% to about 20% by weight of a hair growth orhair regrowth compound (such as minoxidil or pharmaceutically acceptableaddition salts thereof); from about 0.5% to about 10% by weight of anoil phase or oily compound; from about 0% to about 60% of a dihydricalcohol (such as propylene glycol); and from about 0 to about 65% byweight of a C₂-C₄ alcohol (such as ethanol).

Another aspect of the present disclosure is concerned with using thedisclosed compositions to accelerate the onset of the anagen phase ofhair growth in a mammal.

A still further aspect of the present disclosure is concerned with usingthe disclosed compositions to increase the rate at which terminal hairappears on the skin of a mammal.

Another aspect of the present invention is to provide a method ofreducing or preventing hair thinning and hair loss.

Still other aspects and advantages of the present disclosure will becomereadily apparent to those skilled in the art from the following detaileddescription, wherein it is shown and described only in the preferredembodiments, simply by way of illustration of the best mode. As will berealized, the disclosure is capable of other and different embodiments,and its several details are capable of modifications in various obviousrespects, without departing from the spirit of the disclosure.Accordingly, the description is to be regarded as illustrative in natureand not as restricted.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is picture of a microscopic field of view as obtained using aOlympus BX51 Microscope as described below.

FIG. 2 is a freeze-fractured SEM (scanning electron microscopy) pictureof partial cross-section of one of the liquid vesicles contained in thecomposition of Example I (below)

SUMMARY OF THE INVENTION

In certain embodiments, the present invention relates to a compositioncomprising:

-   -   a. liquid vesicles comprise:        -   i. one or more of a hair growth or hair regrowth compound            represented by formulas I or II:

-   -   -   and mixtures thereof, wherein R¹ is hydrogen or —N(R³)(R⁴).            Each R³ and R⁴ individually is selected from the group            consisting of hydrogen, lower alkyl, lower alkenyl, lower            aralkyl, and lower cycloalkyl, and taken together R³ and R⁴            may be a heterocyclic moiety selected from the group            consisting of aziridinyl, azetidinyl, pyrrolidinyl,            piperidino, hexahydroazepinyl, heptamethylenimino,            octamethylenimino, morpholino, and 4-lower-alkylpiperazinyl,            each of said heterocyclic moieties having attached as            substituents on the carbon atoms 0 to 3 lower alkyl groups,            hydroxy or alkoxy, and wherein R² is selected from the group            consisting of hydrogen, lower alkyl, lower alkenyl, lower            alkoxyalkyl, lower cycloalkyl, lower aryl, lower aralkyl,            lower alkaryl, lower alkaralkyl, lower alkoxyaralkyl, and            lower haloaralkyl; tautomers thereof and pharmacologically            acceptable acid addition salts thereof; and        -   ii. a mixture of C₁₂-C₁₅ alkyl lactates;

    -   b. a viscosity modifying agent comprising at least one cellulose        or derivative thereof; and

    -   c. a pharmaceutically acceptable liquid carrier comprising, one        or more solubilizer(s), one or more solubilizing acid(s) or        mixtures thereof;

    -   wherein the liquid vesicles are suspended within the        pharmaceutically acceptable liquid carrier.

In certain embodiments, the present invention relates to a method ofgrowing hair in a subject in need of such treatment, comprisingtopically applying the above described composition to the subject on anarea where hair growth is desired

DETAILED DESCRIPTION OF THE INVENTION

The compositions of the present invention can comprise, consist of, orconsist essentially of the essential elements, steps and limitations ofthe invention described herein, as well any of the additional oroptional ingredients, components, or limitations described herein.

The term “comprising” (and its grammatical variations) as used herein isused in the inclusive sense of “having” or “including” and not in theexclusive sense of “consisting only of.” The terms “a” and “the” as usedherein are understood to encompass the plural as well as the singular.

All documents incorporated herein by reference in their entirety areonly incorporated herein to the extent that they are not inconsistentwith this specification.

All percentages, parts and ratios are based upon the total weight of thecomposition of the present invention, unless otherwise specified. Allsuch weights as they pertain to the listed ingredients are based on theactive level and, therefore, do not include carriers or by-products thatmay be included in commercially available materials, unless otherwisespecified.

The terms “grow” or “growth” as used herein with respect to hair meansthe growth or regrowth of hair. Accordingly, the terms “growth” and“regrowth” are used interchangeably with respect to growing hair orrespect to actives for growing hair.

The term “safe and effective amount” as used herein means an amount of acompound or composition such as a topical or system active sufficient tosignificantly induce a positive benefit, for example, hair growth, butlow enough to avoid serious side effects, i.e., to provide a reasonablebenefit to risk ratio, within the scope of sound judgment of the skilledartisan.

As used herein, the terms “visual inspection” or “visually inspected”means that a human viewer can visually discern the presence of: i) solidor droplet particles in a solution; or ii) hair or hair growth, in eachcase, with the unaided eye (excepting standard corrective lenses adaptedto compensate for near-sightedness, farsightedness, or stigmatism, orother corrected vision) in lighting at least equal to the illuminationof a standard 75 watt incandescent white light bulb at a distance ofabout 0.25 meter.

The term “pharmaceutically acceptable addition salts” meanspharmaceutically acceptable acid or base addition salts. Thepharmaceutically acceptable acid or base addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid and non-toxic base addition salt forms which the compounds offormulas (I and II) are able to form. The compounds of formula (I andII) which have basic properties can be converted in theirpharmaceutically acceptable acid addition salts by treating said baseform with an appropriate acid. Appropriate acids comprise, for example,inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid; sulfuric; nitric; phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic, malonic, succinic (i.e. butane-dioic acid),maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

The compounds of formulas (I and II) which have acidic properties may beconverted in their pharmaceutically acceptable base addition salts bytreating said acid form with a suitable organic or inorganic base.Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, andsalts with amino acids such as, for example, arginine, lysine and thelike.

The terms acid or base addition salt also comprise the hydrates and thesolvent addition forms which the compounds of formula (I and II) areable to form. Examples of such forms are e.g. hydrates, alcoholates andthe like.

For therapeutic use, salts of the compounds of formulas (I and II) arethose wherein the counterion is pharmaceutically acceptable.

In certain embodiments, the present invention as disclosed herein may bepracticed in the absence of any compound or element (or group ofcompounds or elements) which is not specifically disclosed herein.

The composition of the present invention is useful for growing hair. Thecomposition comprises a hair growth active and a C₈-C₂₄ alcohol ester ofa carboxylic acid.

The composition of the present invention is also useful for preventinghair loss and thinning hair.

Hair Growth Compound

The compositions of the present invention further comprise one or moreof a hair growth or hair regrowth compound represented by the Formulas Ior II:

and mixtures thereof.

R¹ is hydrogen or —N(R³)(R⁴). Each R³ and R⁴ individually is selectedfrom the group consisting of hydrogen, lower alkyl, lower alkenyl, loweraralkyl, and lower cycloalkyl, and taken together R³ and R⁴ may be aheterocyclic moiety selected from the group consisting of aziridinyl,azetidinyl, pyrrolidinyl, piperidino, hexahydroazepinyl,heptamethylenimino, octamethylenimino, morpholino, and4-lower-alkylpiperazinyl, each of said heterocyclic moieties havingattached as substituents on the carbon atoms 0 to 3 lower alkyl groups,hydroxy or alkoxy, and wherein R² is selected from the group consistingof hydrogen, lower alkyl, lower alkenyl, lower alkoxyalkyl, lowercycloalkyl, lower aryl, lower aralkyl, lower alkaryl, lower alkaralkyl,lower alkoxyaralkyl, and lower haloaralkyl; tautomers thereof andpharmacologically acceptable acid addition salts thereof (such assulfate salts thereof).

The amount of the compound of the above Formulas I and/or II is a safeand effective amount for promoting hair growth. In certain embodiments,the compound of Formulas I and/or II is present at a concentration offrom 0.1% (or about 0.1%) to 15% (or about 20.0%) of the preparation, oroptionally, from 0.5% (or about 0.5%) to 10% (or about 10%), oroptionally, from 0.5% (or about 0.5%) to 5% (or about 5%), by weight ofthe composition.

Listed below are definitions of various terms used to describe thecompounds of Formulas I and/or II.

The term “lower alkyl” refers to straight or branched chain hydrocarbongroups containing typically 1 to 6 carbon atoms, and more typically 1 to3 carbon atoms.

Examples of suitable lower alkyl groups include methyl, ethyl andpropyl. Examples of branched alkyl groups include isopropyl and t-butyl.Examples of suitable alkoxy groups are methoxy, ethoxy and propoxy.

The “lower cycloalkyl” groups typically contain 3-6 carbon atoms andinclude cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The “lower alkenyl” groups typically contain 2-6 carbon atoms andinclude ethenyl, propenyl and butenyl. The “lower cycloalkenyl” groupstypically contain 3-6 carbon atoms and include cyclopropenyl,cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term “lower aryl” refers to monocyclic or multi-ring aromatichydrocarbon groups typically containing 6 to 14 carbon atoms in the ringportion, such as phenyl, 2-naphthyl, 1-naphthyl, 4-biphenyl, 3-biphenyl,2-biphenyl, and diphenyl groups.

Examples of halo groups are Cl, F, Br and I.

The Mixture of C₈-C₂₄ Alkyl Lactates

The compositions of the present invention also include a mixture ofC₁₂-C₁₅ alkyl lactates.

The mixture of C₁₂-C₁₅ alkyl lactates refers to compositions comprisingC₁₂ alkyl lactates, C₁₃ alkyl lactates, C₁₄ alkyl lactates, and C₁₅alkyl lactates at a ratio of C₁₂ alkyl lactates to C₁₃ alkyl lactates ofabout 1:1 to about 1:2; a ratio of C₁₃ alkyl lactates to C₁₄ alkyllactates of about 1:1 to about 1:2; and a ratio of C₁₄ alkyl lactates toC₁₅ alkyl lactates of about 1:1 to about 1:2 (other components such asC₁₂ alcohols, C₁₃ alcohols, C₁₄ alcohols, and/or C₁₅ alcohols may,optionally, be present in the mixture). Such mixtures are available fromAshland (NJ, USA).

In certain embodiments, the mixture C₁₂-C₁₅ alkyl lactates is present inthe composition in an amount of from 0.5% (or about 0.5%) to 10% (orabout 10%), optionally, from 1.0% (or about 1.0%) to 5% (or about 5%),or, optionally, from 1.5% (or about 1.5%) to 3% (or about 3%), by weightof the composition.

Viscosity Modifying Agent

In certain embodiments, the compositions of the present inventionfurther comprise a viscosity modifying agent comprising a cellulose orcellulose derivative (including the anionic carboxymethylcellulose andthe nonionic celluloses mentioned below).

More specifically, in certain embodiments where the compositioncomprises from about 5% to about 30%, optionally from about 10% to about25%, or, optionally, from about 15% to about 25%, by weight, alcohol (asdescribed herein and, in certain embodiments, ethanol); from about 0 toabout 40% , optionally from about 5% to about 30%, or optionally about10% to about 20%, by weight, glycol (such as propylene glycol orpentylene glycol); from about 0.1 to about 10%, optionally from about0.5% to about 5%, or optionally about 1% to about 3%, by weight, C₈-C₂₄alcohol ester of a carboxylic acid (as described herein); and from about1% to about 15%, optionally from about 2% to about 10%, or optionallyfrom about 2% to about 5%, by weight, minoxidil (or a pharmacologicallyacceptable acid addition salts thereof), storage stability of thecompositions at temperatures both above 30° C. and below 5° C. can beachieved by incorporating a mixture of C₁₂-C ₁₅ alkyl lactates as theC₈-C₂₄ alcohol ester of a carboxylic acid in combination with at leastone cellulose derivative (including the anionic carboxymethylcelluloseand the nonionic celluloses mentioned below)

Useful cellulose of cellulose derivatives include, but are not limitedto, nonionic celluloses or cellulose derivatives such as hydroxylalkylcellulose polymers (e.g., hydroxyl C₁-C₃ alkyl cellulose polymers) andalkyl hydroxylalkyl cellulose polymers (e.g., C₉-C₁₆ alkyl hydroxylC₁-C₃ alkyl cellulose polymers) such as hydroxyethyl cellulose,hydroxypropyl cellulose, cetyl hydroxyethyl cellulose; methyl celluloseand its derivatives such as hydroxymethylcellulose derivatives such ashydroxypropyl methylcellulose (HPMC) and hydroxybutyl methyl celluloseand anionic cellulose derivatives such as methyl cellulose (orderivatives thereof such as carboxymethyl cellulose (CMC)).

In certain embodiments, from 0.1% (or about 0.1%) to 20% (or about 20%),optionally, from 0.5% (or about 0.5%) to 15% (or about 15%), or,optionally, from 1% (or about 1%) to 5% (or about 5%), by weight of thecomposition, of the mixture of C₁₂-C ₁₅ alkyl lactates is incorporatedwith from 0.01% (or about 0.01%) to 5% (or about 5%), or, optionallyfrom 0.1% (or about 0.1%) to 4% (or about 4%), optionally, from 1% (orabout 1%) to 3% (or about 3%), or, optionally from 0.5% (or about 0.5%)to 2% (or about 2%), by weight of the composition, of the at least onecellulose or cellulose derivative.

Without being limited by theory, it is believed that embodiments of thecompositions of the present invention comprising from about 0.1% toabout 20% (optionally, from about 0.5% to about 15%, or optionally, fromabout 1% to about 10%) by weight of a pharmaceutically acceptableaddition salt of the hair growth or hair regrowth compounds of formulasI or II (in certain embodiments, the pharmaceutically acceptableaddition salt of minoxidil); from about 0.5% to about 10% (optionally,from about 2% to about 7.5%) by weight of an oil phase or oily compound;and from about 0 to about 25% (optionally from about 1% to about 25%, oroptionally from about 5% to about 20%) by weight of a C₂-C₄ alcohol(optionally ethanol), collectively, increase the difficulty of achievingstorage stability. The present inventor has discovered that achievingstorage stability is facilitated by incorporating a viscosity modifyingagent comprising a mixture of C₁₂-C1 ₁₅ alkyl lactates as the C₈-C₂₄alcohol ester of a carboxylic acid in combination with at least onecellulose or cellulose derivative (including the anioniccarboxymethylcellulose and the nonionic celluloses mentioned above).

Term “oil phase” or “oily phase” means any non-polar liquid phase whichis immiscible with aqueous liquids (or not water-soluble). In certainembodiments, the oil phase comprises at least one oily compound such asthe C₈-C₂₄ alcohol ester of a carboxylic acid (e.g., cetyl lactate,myristyl lactate) and, optionally, long chain fatty acids such as thesteareth-10. Other components that may be comprised in the oil phase arevolatile oils and non-volatile oils. As used herein the term “oily”,means a hydrophobic and water immiscible.

The term “storage stable” or “storage stability” when referring to acomposition of the present invention, means a composition (such as asolution, emulsion or microemulsion) which is uniform and homogeneousand which is not separated into two or more distinct phases upon visualinspection after the composition is stored in closed, airtight glasscontainers for at least 1 week, optionally at least 7 weeks, at aconstant temperature of 40° C. in a standard laboratory oven (forexample, a Fisher Scientific Isotemp Oven, Model 655F Wadesboro, N.C.,USA, and for at least 3 days at a constant temperature of 5° C. in astandard laboratory refrigerator (for example, VWR refrigerator modelR411GA16, manufactured by Kendro Laboratory Products, Asheville, N.C.,USA,). The above described storage of the composition at 40° C. and at5° C. can occur either separately or sequentially. Relative humidity isnot controlled for during such storage since the storage takes place inclosed glass containers whose walls and closures are impervious to thepassage of water vapor.

According to the ICH Harmonized Tripartite Guideline “Stability Testingof New Drug Substances and Products Q1A(R2), storage at 25° C. for aperiod of time is indicative of stability of the formulation ortherapeutic agent for twice this period of time at 5° C. See also DrugStability, Principles and Practices, Third Edition, Jens T. Cartensen,Chris T. Rhodes, published by Marcel Dekker. Assuming an Arrheniusdependence for the degradation kinetics, an increase of 10° C.accelerates the effective period of storage by approximately a factor of2. Hence, the ICH guidelines estimate that 13 weeks at 40° C. isequivalent to 2 years at room temperature (or 25° C.). This conversiontherefore allows that 13 weeks storage at 40° C. and 60% relativehumidity is similar to a 2 years shelf-life for a formulation at 25° C.

In addition to the viscosity modifying agents mentioned above, otherviscosity modifying agent may further be added to impart viscosityand/or shear thinning properties to the compositions of the presentinvention. Suitable additional viscosity enhancing agents include, butare not limited to:

(a) ionic polymers including cationic polymers such as quaternaryammonium compounds, polyquaternium compounds and quaternium siliconecompounds and anionic polymers such as carboxymethyl cellulose (CMC)(the same or different from that referenced above).

Examples of suitable quaternary ammonium compounds include, but are notlimited to, polyquaternium compounds; distearyldimonium chloride;dipalmitoylethylhydroxyethylmonium chloride; dioleoylethyl dimethylammonium methosulfate; dioleoylethyl hydroxyethylmonium methosulfate;dilinolamidopropyldimonium chloride; dioleylethyl hydroxyethylmoniumchloride; dipalmitoylethyldimonium chloride; cocodimoniumhydroxypropyloxyethyl cellulose; lauryldimonium hydroxypropyloxyethylcellulose; stearyldimonium hydroxyethyl cellulose; stearyldimoniumhydroxypropyl oxyethyl cellulose; quaternium proteins such ashydroxypropyltrimonium hydrolyzed collagen, lauryldimonium hydroxypropylhydrolyzed collagen, cocodimonium hydroxypropyl hydrolyzed collagen,stearyltrimonium hydroxyethyl hydrolyzed collagen, stearyidimoniumhydroxypropyl hydrolyzed collagen, hydroxypropyltrimonium hydrolyzedkeratin, cocodimonium hydroxypropyl hydrolyzed hair keratin,cocodimonium hydroxypropyl hydrolyzed keratin, hydroxypropyltrimoniumgelatin, hydroxypropyltrimonium hydrolyzed casein; quaternary starchessuch as hydroxypropyltrimonium hydrolyzed wheat starch,hydroxypropyltrimonium hydrolyzed corn (maize) starch,hydroxypropyltrimonium hydrolyzed potato starch, hydroxypropyltrimoniumhydrolyzed amylopectin; Quaternium-33 (quaternary lanolin); quaternaryguar derivatives such as guar hydroxypropyltrimonium chloride,hydroxypropyl guar hydroxypropyltrimonium chloride; quaternary naturaland plant actives (sugar derivatives) such as choline; and mixturethereof.

Examples of suitable polyquaternium compounds include, but are notlimited to, Polyquaternium 6, Polyquaternium 7 (co-polymer ofdiallylmethyl ammonium chloride), Polyquaternium 10 (quaternizedhydroxyethylcellulose polymer), Polyquaternium 11, Polyquaternium 16,Polyquaternium 22, Polyquaternium 28, Polyquaternium 29 (quaternarychitosan), Polyquaternium 37, Polyquaternium 42, Polyquaternium 44,Polyquaternium 50 and mixtures thereof. Commercial examples includePolymer JR type from Amerchol such as Polyquaternium 10, Cosmedia Ultra300 or Cosmedia SP (Polyquaternuim 37) from BASF, or cationic guar gumknown Guar hydroxypropyl trimonium chloride with trade name N-Hance andAquatCat from Ashland.

The cationic polymers may also include the quaternized products of graftpolymers from organopolysiloxanes and polyethyl oxazolines described inU.S. Pat. No. 5,472,689 and U.S. Pat. No. 5,747,016, both of whichpatents are hereby incorporated by reference.

In addition to the carboxymethyl celluloses, anionic polymers caninclude homopolymers and copolymers of carboxymethyl monomers, and inparticular homopolymers and copolymers of (meth) acrylic acid, such as:polyacrylic acid, acrylic acid/ethyl acrylate copolymers, acrylicacid/polyallyl sucrose copolymers and mixtures thereof.

(b) nonionic polymers such as polysaccharides or polysaccharidederivatives and in particular: celluloses and derivatives thereof, suchas hydroxyalkyl cellulose polymers and alkyl hydroxyalkyl cellulosepolymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, cetylhydroxyethyl cellulose; methyl cellulose and its derivatives such ashydroxymethylcellulose derivatives such as hydroxypropyl methylcellulose(HPMC) and hydroxybutyl methyl cellulose (the same or different fromthat referenced above); natural or synthetic gums and their derivatives,and in particular xanthan gum, guar gum, and pectin; starch and starchderivatives; chitin such as chitosan; xyloglucan; polyvinylalcohol;polyvinylpyrrolidone; or their derivatives.

Nonionic polymers also include poloxamers having the following formula:

where “x” represents the average number of PEO units and is an integerof from about 80 to about 140, optionally about 90 to about 120, oroptionally from about 95 to a about 110; “y” represents the averagenumber of PPO units is an integer of from about 40 to 80, optionallyfrom about 50 to about 70 and the ratio of “x” to “y” is no greater than4:1 (or about 4:1), optionally 3:1 (or about 3:1), optionally 2.8:1 (orabout 2.8:1), optionally 2:1 (or about 2:1), or optionally 1:1 (or about1:1), yet the ratio of “x” to “y” is at least 2:1 (or about 2:1), oroptionally 3:1 (or about 3:1). Suitable examples of such poloxamers aredescribed below:

“y” “x” Pluronic (Average (Average (supplied No. of PPO No. of PEOPoloxamer by BASF) units) units) 338 F108 50.3 132.7 407 F127 65.2 100.2

In certain embodiments, the viscosity modifying agent is a cationicpolymer such as polyquaternium-37. Such a viscosity modifying agent isfor example commercially available from Cognis under the trademark nameUltragel 300 and from Ciba under the trademark name Salcare.

In certain embodiments, the viscosity modifying agent is an anionicpolymer such as carboxymethyl cellulose. Such a viscosity modifyingagent is for example commercially available from CP Kelco under thetrademark name FinnFix or Dow Chemical under the tradename Walocel™.

In certain embodiments, the viscosity modifying agent is nonionicpolymer such as poloxamer. Such a viscosity modifying agent is forexample commercially available from BASF under the trademark namePluronic.

In certain embodiments, the viscosity modifying agent is nonionicpolymer such as hydroxypropylmethyl cellulose. Such a viscositymodifying agent is for example commercially available from Dow Chemicalunder the trademark name Methocel E10M premium CR HPMC.

In certain embodiments, the viscosity modifying agent is selected from(or the group consisting of),but not limited to, cationic polymers suchas polyquaternium 37, polyquaternium 7, polyquaternium 4, polyquternoium10; anionic polymers such as carboxymethylcellulose; non-ionic polymerssuch as hydroxypropylmethyl cellulose and poloxamer 407; or mixturesthereof.

In certain embodiments, the viscosity modifying agent is a mixture of anonionic polymer as described herein and an ionic polymer, including thecationic and anionic polymers, as described herein.

In certain embodiments, the viscosity modifying agent is a mixture oftwo or more of polymers selected from (or, the group consisting of), butnot limited to, cationic polymers such as polyquaternium 37,polyquaternium 7, polyquaternium 4, polyquternoium 10; anionic polymerssuch as carboxymethylcellulose; non-ionic polymers such ashydroxypropylmethyl cellulose and poloxamer 407; or mixtures thereof.

In certain embodiments, the viscosity modifying agent is a mixture oftwo or more of the carboxymethylcellulose, hydroxypropylmethyl celluloseand poloxamer 407.

The viscosity modifying agent(s) is (are) employed in an amountsufficient to provide the inventive composition with a viscosity suchthat when the composition is applied to the scalp and/or hair, thecomposition does not easily drip down the scalp or hair fibers in afluid-like manner and it is able to hold the fibers together during thetreatment or application period.

At the same time, the viscosity of the inventive composition is suchthat it is easy to spread or apply onto the hair fibers in a uniformmanner as well as permit easy combing of hair.

The viscosity modifying agent(s) may be used in concentrations rangingfrom about 0.1% to about 10.0% by weight, optionally from about 0.5% toabout 5.0% by weight, or optionally from about 1.0% to 5.0% by weight ofthe total composition.

In certain embodiments, the compositions of the present invention have aviscosity of from about 50 cps to about 30000 cps, optionally from about100 cps to about 15000 cps, or optionally from about 500 cps to about10000 cps as measured using a Brookfield RV (spindle 4, speed 6 RPM at 1minute following the temperature equilibration at 25° C.±1° C.).

In certain embodiments, the compositions of the present invention have aviscosity of less than about 10000 cps, or optionally from about 50 cpsto about 8000 cps, optionally from about 100 cps to about 6000 cps asmeasured using a Brookfield RV (spindle 4, speed 6 RPM at 1 minutefollowing the temperature equilibration at 25° C.±1° C.).

Alternatively, in certain embodiments, where the composition comprisesfrom about 5% to about 65%, optionally from about 10% to about 60%, oroptionally, from about 15% to about 35%, by weight, alcohol (asdescribed herein and, in certain embodiments, ethanol); from about 0 toabout 40% , optionally from about 5% to about 30%, or optionally about10% to about 20%, by weight, glycol (such as propylene glycol orpentylene glycol); from about 0.1 to about 10% , optionally from about0.5% to about 5%, or optionally about 1% to about 3%, by weight, C₈-C₂₄alcohol ester of a carboxylic acid (as described herein and, in certainembodiments, cetyl lactate, myristyl lactate or mixtures thereof); andfrom about 1% to about 15%, optionally from about 2% to about 10%, oroptionally from about 2% to about 5%, by weight, minoxidil (or apharmacologically acceptable acid addition salts thereof), storagestability of the compositions at temperatures both above 30° C. andbelow 5° C. can be achieved by incorporating a viscosity modifying agentcomprising a nonionic hydroxypropylmethyl cellulose and a high molecularweight carboxymethyl cellulose at a ratio of the nonionichydroxypropylmethyl cellulose to the high molecular weight carboxymethylcellulose of greater than 1:1 (or about 1:1), optionally 3:1 (or about3:1). In certain embodiments, the ratio of nonionic hydroxypropylmethylcellulose to high molecular weight carboxymethyl cellulose is no greaterthan 10:1 (or about 10:1), wherein the total concentration of thenonionic hydroxypropylmethyl cellulose and high molecular weightcarboxymethyl cellulose is from 0.5% (or about 0.5%) to 3% (or about3%), optionally from 0.85% (or about 0.85%) to 1.25% (or about 1.25%),by weight of the total composition.

The term “high molecular weight carboxymethyl cellulose” means acarboxymethyl cellulose having: i.) a carboxymethyl degree ofsubstitution (C.M.D.S.) (which is average number of ionizablecarboxymethyl ether groups per repeating anhydroglucose chain unit ofthe cellulose molecule) of from 0.4 (or about 0.4) to 1.5 (or about1.5), optionally from 0.6 (or about 0.6) to 0.9 (or about 0.9), oroptionally 0.7 (or about 0.7); ii.) an average degree of polymerizationof from about 2000 to about 4000, optionally from about 2500 to about3500, or optionally 3200 (or about 3200); and iii) a weight averagemolecular weight of from about 600,000 to about 800,000, optionally fromabout 650,000 to about 750,000, or optionally from about 675,000 toabout 730,000. Suitable high molecular weight carboxymethyl celluloseare supplied by Ashland (Wilmington, Del.) under the tradenames Aqualon®CMC 7HF, Aqualon® CMC-7H4, Aqualon® CMC-7H3 S, Aqualon® CMC-7HOF andAqualon® CMC-7H. In certain embodiments, the high molecular weightcarboxymethyl cellulose is Aqualon® CMC 7HF.

In certain embodiments, the viscosity modifying agents also impartsshear thinning properties to the compositions of the present invention.Shear thinning is a term used in rheology to describe non-Newtonianfluids which have decreased viscosity when subjected to shear strain. Asused herein, the “shear-thinning viscosity” of the compositions of thepresent invention refers to the pseudo plastic-like property of thecompositions such that the compositions upon application of a shearstress (e.g., from pumping or pouring, dispensing during manufacture ordistribution/application of the compositions) changes viscosity andbecomes less thick and flows more like water. As used herein, the “yieldstress value” refers to the minimum amount of shear stress (such as, asa result of application by pumping, pouring or otherdistribution/application of the compositions) necessary before the flowof the compositions begin or, alternatively, the point where the viscousmodulus G″ of the composition becomes larger than the storage modulusG′. In certain embodiments the compositions of the present inventionhave a shear-thinning viscosity and a yield stress value such that whenthe composition is applied to the mammal skin e.g. scalp, the shearcreated by the application action (e.g., by either finger(s) or anapplicator such as a roller or a dropper, or a brush) will allow thecomposition to thin and spread out evenly over the treatment surface.Once applied the composition regains its higher viscosity which avoidsdrips and runs on the scalp or face.

The shear thinning property of the compositions of the present inventioncan also be described in terms the composition's shear thinning index(as described below).

Shear Thinning Measurement Procedure

Rheological measurements were performed (TA Instruments ARES G2Rheometer). Yield stress values were measured by performing strainsweeps at 1 rad/s, and taking the yield stress value as the point wherethe viscous modulus G″ became larger than the storage modulus G′ uponincreasing oscillatory stress. Frequency sweeps were performed from 100to 0.1 rad/s at a strain in the linear viscoelastic regime. Flow curvesteps were performed by stepping the shear rate from 0.1 to 1000 s⁻¹ andallowing the torque to reach a steady value for each point.

${{Shear}\mspace{14mu} {thinning}\mspace{14mu} {index}} = \frac{a\mspace{14mu} {first}\mspace{14mu} {viscosity}}{a\mspace{14mu} {second}\mspace{14mu} {viscosity}}$

Wherein the first viscosity is measurement obtained from the first shearrate of 1 s⁻¹ and the second viscosity is the measurement obtained fromthe second shear rate of 450 s⁻¹.

The above mentioned rheological properties for the composition ofExample 1 were determined to be as follows:

Yield stress Viscosity at Viscosity at Shear value 1 s⁻¹ 450 s⁻¹Thinning (Pa · s) (Pa · s) (Pa · s) Index Composition of 0.93 7.3 0.3322.1 Example 1

In certain embodiments, the compositions of the present invention have aviscosity at a shear rate of 1 s⁻¹ of from about 0.1 Pa·s to about 15Pa·s, or optionally from about 1 Pa·s to about 10 Pa·s.

In certain embodiments, the compositions of the present invention have aviscosity at a shear rate of 450 s⁻¹ of from about 0.01 Pa·s to about 1Pa·s, or, optionally from about 0.1 Pa·s to about 0.5Pa·s.

In certain embodiments, the compositions of the present invention have ayield stress value of from about 0.01 Pa·s to about 5 Pa·s, optionallyfrom about 0.1 Pa·s to about 2.0 Pa·s, or optionally from about 0.1 Pa·sto about 0.95 Pa·s.

In certain embodiment, the compositions of the present invention have ashear thinning index of 10 or more, optionally, of 20 or more,optionally from about 10 to about 500, optionally from about 20 to about100, or optionally from about 20 to about 50.

Pharmaceutically Acceptable Topical Carriers

The topical compositions useful in this invention contain formulationssuitable for topical application to skin and scalp. The term “topical”as employed herein relates to the use of a composition along with asuitable pharmaceutical carrier, and applied according to the method ofthe present invention at the site of hair loss, reduced hair growth orbaldness for exertion of local action. Accordingly, such topicalcompositions useful in the methods of the present invention includethose pharmaceutically acceptable forms in which the compound is appliedexternally by direct contact with the skin surface to be treated.

The compositions of the present invention contain the C₈-C₂₄ alcoholester of a carboxylic acid and the hair growth compound in apharmaceutically acceptable topical carrier. The phrase“pharmaceutically acceptable”, as used herein, denotes compatibilitywith the active contemplated herein, including the hair growth actives.The pharmaceutically acceptable topical carriers are also compatiblewith the skin, scalp and any keratinous substrates.

Accordingly, the pharmaceutically acceptable topical carrier isformulated such that upon mixing with the C₈-C₂₄ alcohol ester of acarboxylic acid, the combined mixture is a multiple phase mixture withthe C₈-C₂₄ alcohol ester of a carboxylic acid forming one phase and thepharmaceutically acceptable topical carrier forming separate phase. Incertain embodiments, the multiple phase mixture is a bi-phasic mixture.

In certain embodiments, the pharmaceutically acceptable topical carrierof the present invention includes one or more solubilizers for the hairgrowth compound. Suitable solubilizers include, but are not limited,monohydric or polyhydric simple alcohols, including, but not limited to,water, C₁-C₃ alcohols (such as methanol, ethanol, n-propanol,isopropanol), n-butanol such as 1-butanol, n-hexanol, 2-ethyl-1-hexanol,polyhydric alcohols (such as ethylene glycol, propylene glycol,polypropylene glycol [e.g., polyethylene glycol 200 (PEG 200),polyethylene glycol 400 (PEG 400)], pentylene glycol, the butanediolisomers, 1,5 pentane diol, 1,2,6-trihydroxyhexane, 12-ethyl-1,3-hexanediol, 1,7-hepatanediol, or glycerin); ether alcohols,such as, for example, 1-methoxy-2-propanol,3-ethyl-3-hydroxymethyloxetan, tetrahydrofurfuryl alcohol, ethyleneglycol monomethyl ether, ethylene glycol monoethyl ether, ethyleneglycol monobutyl ether, diethylene glycol monomethyl ether, diethyleneglycol monoethyl ether, diethylene glycol monobutyl ether, diethyleneglycol or dipropylene glycol; solubilizers such as xylene,chlorobenzene, ethyl acetate, butyl acetate, diethylene glycol dimethylether, dipropylene glycol dimethyl ether, ethylene glycol monomethyl ormonoethyl ether acetate, diethylene glycol ethyl and butyl etheracetate, propylene glycol monomethyl ether acetate,1-methoxypropyl-2-acetate, 3-methoxy-n-butylacetate, propylene glycoldiacetate, N-methylpyrrolidone and N-methylcaprolactam, tocopherylpolyethylene glycol succinate (TPGS), dimethylformamide (DMF),dimethylacetamide (DMA), capryl-caproyl macrogol 8-glyceride (Labrasol)or mixtures of any of the above mentioned solubilizers.

In certain embodiments, the solubilizer of the present invention isselected from one or more C₁-C₃ alcohol(s) such as ethanol, n-propanol,isopropanol; one or more polyhydric alcohol(s) such as propylene glycol,polypropylene glycol, pentylene glycol, glycerin; ethyl acetate andmixtures thereof. In certain embodiments, the solubilizer of the presentinvention comprises ethanol, isopropanol, pentylene glycol, propyleneglycol, ethyl acetate, polyethylene glycol and mixtures thereof.

In certain embodiments, the one or more solubilizer(s) is present in thecomposition in an amount of from about 0.1% to about 60%, optionally,from about 0.1% to about 50%, or, optionally, from about 0.1% to about40%, by weight of the total composition.

In certain embodiments, the one or more C₁-C₃ alcohol(s) are present inthe composition in an amount of from about 0.1% to about 40%,optionally, from about 1% to about 30%, or, optionally, from about 10%to about 25%, by weight of the total composition.

In certain embodiments, the one or more polyhydric alcohol(s) is presentin the composition in an amount of from about 0.1% to about 40%,optionally, from about 1% to about 30%, or, optionally, from about 5% toabout 25%, by weight of the total composition.

In certain embodiments, the compositions of the present inventionfurther comprise water in an amount of from about 5% to about 60%,optionally, from about 10% to about 50%, or, optionally, from about 20%to about 40%, by weight of the total composition.In certain embodiments,to obtain “clear” compositions, monohydric (such as ethanol, propanol,isopropanol and mixtures thereof) and dihydric (such as propyleneglycol, butylene glycol, pentylene glycol and mixtures thereof)alcoholic solubilizers are incorporated at a total concentration of fromabout 20% to about 90%, optionally from about 30% to about 80%,optionally from about 35% to about 80%, optionally, from about 40% toabout 75%, or, optionally, from about 50% to about 70%, by weight of thetotal composition.

The term “clear” as used herein means a solution or gel composition freeof or substantially free of particles or droplets greater than 2 microns(optionally, 1 micron). The term “substantially free” as used withrespect to particles or droplets greater than 2 microns (optionally, 1micron) means solution or gel compositions having less than 20,optionally 10, or optionally 5 of particles or droplets greater than 2microns (optionally, 1 micron) per 0.5 mm² field of view when viewed bya high magnification microscope (such as an Hirox RH-2000E withMXB-5000REZ lens).

The term clear also means a solution or gel composition free of orsubstantially free of turbidity when visually inspected. The term“turbidity” as used herein means the cloudiness or haziness of a fluidcaused by individual particles (suspended solids or liquids) that aregenerally invisible to the unaided eye. Fluids can contain suspendedsolid or liquid matter consisting of varying particle size. While somesuspended material will be large enough and heavy enough to settlerapidly to the bottom of the container (or separate into distinctlayers) if a liquid sample is left to stand, very small particles willsettle (or separate out) only very slowly or not at all if the sample isregularly agitated or the particles are colloidal. These small solid orliquid particles cause the liquid to appear turbid.

One property of such solid or liquid particles is that they will scattera light beam focused on them. This light scattering effect is considereda good measure of turbidity in water. Turbidity measured this way usesan instrument called a Turbidimeter with the detector setup to the sideof the light beam. The more particles floating in water, the more lightis scattered toward the detector and the higher the value of detectedlight. A lower value of detected light indicates a clearer or lesscloudy solution. The units of turbidity from a calibrated Turbidimeter(such as ‘’'a Laboratory Turbidimeter HACH Model 2100N operating atambient temperature [20° C.]) are called Nephelometric Turbidity Units(NTUs). A clear formulation is defined as a formulation with an NTU ofless than 10 (or about 10), optionally less than 8 (or about 8), oroptionally less than 6 (or about 6).

In certain embodiments, where the composition comprises a C₁₂-C₁₈ alkyllactate, the clarity of the composition is dependent upon theconcentration of the C₁₂-C₁₈ alkyl lactates. The relationship can bedefined in terms of the following “relative dielectric constant index”(RI) equation:

RI=(D1/D2)/% concentration of C₁₂-C₁₈ alkyl lactate (as percentage oftotal composition)

Where:

D1=the total dielectric constant of all non-aqueous solvents

D2=the total dielectric constant of aqueous solvents/the conc.

The present inventor has found that compositions having an RI value ofgreater than 0.15 were determined to be clear compositions.

In certain embodiments, the hair growth compounds are dissolved in orcontain as auxiliary components one or more solubilizing acid(s) whichdissolve minoxidil (and other compounds of formulas I and II) such ascitric acid, acetic acid, succinic acid, maleic acid, benzoic acid,lactic acid, tartaric acid, barbituric acid, protocatechuic acid, gallicacid, 5-nitro-2-furoic acid, alpha-keto acids and mixtures thereof. Incertain embodiments, the solubilizing acids are selected from citricacid, lactic acid, alpha-keto acids or mixtures thereof.

When used, the lactic acid or lactate may be selected from the groupconsisting of lactic acid, salts of lactic acid, pro-drugs of lacticacid, and mixtures thereof. The salts of lactic acid may include, but isnot limited to, alkali salts and alkaline earth salts. In certainembodiments, the lactate is selected from the group consisting of lacticacid, lithium lactate, sodium lactate, potassium lactate, magnesiumlactate, calcium lactate, zinc lactate, manganese lactate, and the like,and mixtures thereof In other embodiments, the lactate is selected fromthe group consisting of lactic acid, sodium lactate, potassium lactate,magnesium lactate, calcium lactate, zinc lactate, manganese lactate, andmixtures thereof. In still further embodiments, the lactate is lacticacid. Additionally or alternatively, an alpha-keto acid may be used asthe auxiliary component acid. In certain embodiments, the alpha-ketoacid is a pyruvic acid selected from the group consisting of pyruvicacid, lithium pyruvate, sodium pyruvate, potassium pyruvate, magnesiumpyruvate, calcium pyruvate, zinc pyruvate, manganese pyruvate, methylpyruvate, salts thereof, prodrugs thereof, and mixtures thereof.

When present in the compositions of the present invention, the one ormore solubilizing acid(s) is present in an amount suitable fordissolving the hair growth compound. In certain embodiments, the one ormore solubilizing acid(s) is present in the composition in an amountfrom about 0.1% to about 10%, optionally, from about 0.5% to about 7.5%,or, optionally, from about 1.0% to about 5.0%, by weight of thecomposition.

In certain embodiments, the pharmaceutically acceptable topical carrierof the present invention includes one or more emulsifier(s). Emulsifiersmay be nonionic, anionic, cationic, and/or polymeric. Examples ofsuitable emulsifiers include, but are not limited to, those typicallyidentified as such in the art of personal care and cosmeticformulations, e.g., cationic emulsifiers such as distearyldimoniumchloride, non-ionic emulsifiers such as steareth-2, steareth-21,glyceryl stearate, glyceryl laurate, lecithin, glycol stearate, glycolstearate SE, glycol distearate, sorbitan esters, such as sorbitantrioleate, sorbitan oleate, sorbitan stearate, ceteth-2, PEG-30dipolyhydroxystearate, PEG-4 dilaurate, Laureth-4, PEG-7 glycerylcocoate, polysorbate 85, PEG-100 stearate, PEG-8 laurate, PEG-8 oleate,polysorbate 60, polysorbate 80, cetearyl glucoside, Oleth-20, Ceteth-20,PEG-25 hydrogenated castor oil stearamide MEA, stearyl alcohol, cetylalcohol; anionic emulsifiers such as potassium cetyl phosphate;polymeric emulsifiers such as acryloyldimethyltaurate/VP copolymers, andthe like and mixtures of any of the above emulsifiers.

In certain embodiments, the emulsifier of the present invention isselected from the group consisting of steareth-2, glyceryl stearate,polysorbate 60, polysorbate 80, stearyl alcohol, cetyl alcohol andmixtures thereof. In certain embodiments, the emulsifier of the presentinvention is steareth-2, polysorbate 60 and mixtures thereof.

In certain embodiments, the one or more emulsifier(s) is present in thecomposition in an amount from about 0.1% to about 15%, optionally, fromabout 0.1% to about 10%, or, optionally, from about 0.1% to about 5%, byweight of the total composition.

In certain embodiments, the pharmaceutically acceptable topical carriercan be in any product form, including ointments, pastes, gels, jellies,serums, aerosol and non-aerosol sprays, foams, creams, lotions,solutions, toners, suspensions, leave-on conditioners, and the like. Theterm “ointment” embraces formulations (including creams) havingoleaginous, absorption, water-soluble and emulsion-type bases, e.g.,petrolatum, lanolin, polyethylene glycols, as well as mixtures of these.A more detailed discussion of the specific carriers and additionalcomponents useful in the compositions of the present invention can befound in U.S. Patent Publication 2008/0145331 to Bruning et al., hereinincorporated by reference in its entirety. In one embodiment, thepharmaceutically -acceptable topical carrier constitutes from about 50%to about 99.99%, by weight, of the composition or optionally from about80% to about 95%, by weight, of the composition.

Alternatively, rinse off carrier forms such as shampoos, cream rinses,conditioners, cleansers and cleansing lotions may also be used.

Vesicles

The compositions of the present invention also comprise one or morevesicles. In certain embodiments, the vesicles are liquid vesicles. Incertain embodiments, the vesicles are non-phospholipid vesicles. FIG. 1is a picture of a microscopic field of view as obtained using a OlympusBX51 Microscope (as described below) showing the liquid vesiclescontained in the composition of Example 1 (below).

In certain embodiments, the vesicle has an average diameter of fromabout 0.05 μm to about 20 μm, optionally from about 0.1 μm to about 15μm, or optionally from about 0.3 to about 10 μm. Measurement of theaverage diameter of the vesicles of the present invention is describedin more detail below. In certain embodiments, the vesicles aremultilayer (i.e., have at least two layers) where the layers have alayer thickness of about 0.01 μm to about 2 preferably about 0.05 μm toabout 1 μm.

The following procedure can be used to determine the average diameter ofvesicles in the microscopic field of view as depicted in FIG. 1:

A transmission microscope equipped with conventional CCD cameratechnology (i.e., Olympus BX51 Microscope, Magnification 100×) was usedto obtain a magnified field of view to acquire a microscopic image ofthe vesicles. The vesicles within the magnified field of view of themicroscope are detected and their corresponding diameters were measuredby the accompanying image analysis software of the microscope (i.e.,analySIS image software, Olympus Soft Imaging Solutions GmbH).

The statistical analysis output for the magnified field view of FIG. 1that was obtained using the above described image analysis software isshown in Table A below. It was found that average diameter of thevesicles in the magnified field of view of FIG. 1 was about 0.7±0.83

TABLE A Parameter Value Count (the total number of vesicles 2918detected in the magnified field of view of FIG. 1) Average Diameter 0.70 μm Minimum Diameter  0.13 μm Maximum Diameter 10.81 μm StandardDeviation of Average Diameter  0.83 μm

The vesicle shown in FIG. 1 has an average diameter of 0.7 μm, with aminimum diameter of 0.13 μm and maximum diameter of 10.8 μm.

FIG. 2 shows a freeze-fractured SEM (scanning electron microscopy)picture of partial cross-section of one of the liquid vesicles containedin the composition of Example I (below).

FIG. 2 also depicts the multiple layers of the liquid vesicle, showinglayer thicknesses “a” and “b”. The layer thickness “a” is about 0.4 μmand the layer thickness “b” is about 0.2 μm as measured using the “2 μm”measurement scale depicted at the bottom the picture of FIG. 2.

The C₈-C₂₄ alcohol ester of a carboxylic acid and/or the hair growthcompound can be present in either the vesicle or the pharmaceuticalacceptable topical carrier, or in both the vesicle and thepharmaceutical acceptable topical carrier.

Optional Ingredients

Additional Actives

In certain embodiments, the compositions of the present invention may,optionally, further include active agent selected from the groupconsisting of additional hair growth actives, anti-acne agents,antimicrobial agents, anti-fungal agents, antibiotic or antisepticagents, antipsoriatic agents, anti-viral agents, anti-seborrea agents,anti-dandruff agents, active agents for treating keratosis pilaris,anti-inflammatory agent, vasodilators, UV absorbers and anti-canceragents.

In certain embodiments, the compositions of the present inventioninclude additional hair growth actives. In certain embodiments, theadditional hair growth active selected from a group of compounds knownto promote hair growth and available as drugs, such as diazoxide,pinacidil, bimatoprost, finasteride, a type 2 5-alpha-reductaseinhibitor, and dutasteride, a type 1- and 2-5-alpha-reductase inhibitor,as well as flutamide, bicalutamide, pregnane derivatives, progesteronederivatives, experimental agents such as FCE 28260 and the like.Spironolactone and other diuretics may also be utilized as it isindicated for women in some cases (also known as aldactone: analdosterone receptor antagonist). Also useful as hair growth agents areazole antifungals as mentioned below. Examples of suitable azoleantifungals include, but are not limited to, miconazole, ketoconazole,econazole, itraconazole, sertaconazole, fluconazole, voriconazole,clioquinol, bifoconazole, terconazole, butoconazole, tioconazole,oxiconazole, sulconazole, saperconazole, clotrimazole, undecylenic acid,haloprogin, butenafine, tolnaftate, nystatin, ciclopirox olamine,terbinafine, amorolfine, naftifine, elubiol, griseofulvin, theirpharmaceutically acceptable salts, and combinations thereof.

Also useful in certain embodiments as the additional hair growth activeare herbal remedies that may have 5-alpha-reductase inhibitory action oractives with inhibitory activity for dihydrotestosterone (DHT) orotherwise induce hair growth may include: saw palmetto, □-sitosterol andPygeum africanum. Other additional hair growth actives that may havesuch activity are beta-sisterol, sepicontrol and licorice,gamma-linolenic acid and other unsaturated fatty acids, zinc, copper andtheir salts, Cotinus coggygria extract, green tea catechin(−)-epigallocatechin gallate (EGCG) and other polyphenols, and the like.Grape seed, apple seed, apple juice, blackberry, millet seed, marioneextract, cysteine, Thuja orientalis extract, Polygonum multiflorumthunberg extract, Espinosilla extract, Hibiscus rosa sinensis flowers,murraya koenigii, hinokitiol, and barley extracts may also be potentialadditional hair growth actives, although they are not thought to be verycommon or satisfactory in achieving satisfactory hair growth results.

The additional hair growth active may also include agents or naturalextracts that activate or inhibit the Wnt or beta-catenin pathway suchas valproic acid (VPA), lithium salts, dihydroquercetin-glucoside(DHQG), epigallocatechin gallate-glucoside, agents or natural extractsthat can accelerate hair follicle growth such as placental growth factor(P1GF), reflexa (C. reflexa) etc, epidermal growth factor (EGF),vascular epithelia growth factor (VEGF), fibroblast growth factors (FGF)such as FGF 5, or FGF9, BMP (bone morphogenetic protein) inhibitors suchas6-(4-(2-(piperidin-1-yl)ethoxy)phenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine,dorsomorphinor mixtures thereof . Inhibitors for TGF-β such asproanthocyanidines like procyanidine B from the flavonoids can also beused.

Additional hair growth actives may also include Prostaglandin D₂inhibitors, or Agents with antiandrogenic properties Cortexolone17a-propionate.

Other additional hair growth actives include prostaglandine analogueslicke vsprostol, or latanoprost, bimatoprost or their deriavtives,extract of red deer antler, Adiantum capillus-veneris Linn. (A.capillus-veneris), ginsenoside F2) and mixtures thereof.

Mixtures of any of the above described additional hair growth activescan also be used.

An anti-acne agent is a compound that has been approved by the U.S. Foodand Drug Administration for the topical treatment of acne. Examples ofsuitable anti-acne agents include, but are not limited to, salicylicacid, benzoyl peroxide, sulphur, retinoic acid, candidabombicola/glucose/methyl rapeseedate ferment, peat water, resorcinol,silt, peat, permethin, azelaic acid, clindamycin, adapalene,erythromycin, sodium sulfacetamide, minocycline, tetracycline,oxycycline, sodium sulfacetamide, dapsone, retinoid such asisotretinoin, tretinoin, ethinyl estradiol, norgestimate, nicotinamide,and their derivatives, and combinations thereof.

Antimicrobial agents are compounds that kill microorganisms or preventor inhibit their growth or reproduction. Examples of suitableantimicrobial agents include, but are not limited to: ethanol, propanol,betains, benzalkonium chloride, benzethonium chloride, lauric arginayte,sugarquat, methyl benzethonium chloride, cetypyridiunium chloride,2,4,4′,-trichloro-2-hydroxy diphenyl ether (Triclosan), parachlorometaxylenol (PCMX), Iodopropynyl butylcarbamate, diazolidinyl urea,chlorhexidene digluconate, chlorhexidene acetate, chlorhexideneisethionate, chlorhexidene hydrochloride, hexetidine, Quaternium 15,triclocarbon, polyhexamethylene biguanide, cetylpyridium chloride,imidazolidinyl urea, diazolidinyl urea,3-iodo-2-propynyl-N-butylcarbamate, 2-methyl-4-isothiazolin-3-one,dimethyl dimethyl hydantoin, (5-chloro-2-(2,4-dichlorophenoxy)phenol,monolaurin glyceryl laurate, camellia sinensis, candidabombicola/glucose/methyl rapeseedate ferment, hydrogen peroxide, phenol,poloxamer 188, PVP-iodine, thiourea, natural antimicrobial agents, suchas cinnamon oil, cinnamaldehyde, lemongrass oil, clove oil, saw palmettoextract, thyme oil white, thyme oil red, thymol, tea tree oil, pinuspinaster bark extract, rosemary leaf extract, grape seed extract, andbetel oil, silver containing compounds, such as silver nitrate, silverlactate, silver citrate, and silver zeolite, antimicrobial fatty acidester of a polyhydric alcohol, a fatty ether of a polyhydric alcohol andalkoxylated derivatives thereof, and combinations thereof.

Antimicrobial agent includes anti-fungal agents such as an azole.Examples include, but are not limited to, miconazole, ketoconazole,econazole, itraconazole, sertaconazole, fluconazole, voriconazole,clioquinol, bifoconazole, terconazole, butoconazole, tioconazole,oxiconazole, sulconazole, saperconazole, clotrimazole, undecylenic acid,haloprogin, butenafine, tolnaftate, nystatin, ciclopirox olamine,terbinafine, amorolfine, naftifine, elubiol, griseofulvin, theirpharmaceutically acceptable salts, and combinations thereof.

Antimicrobial agents include antibiotics or antiseptics. Examples ofthese include, but are not limited to, mupirocin, neomycin sulfatebacitracin, polymyxin B, 1-ofloxacin, tetracyclines such aschlortetracycline hydrochloride, oxytetracycline-10 hydrochloride andtetrachcycline hydrochloride, clindamycin phosphate, gentamicin sulfate,metronidazole, hexylresorcinol, methylbenzethonium chloride, phenol,quaternary ammonium compounds, tea tree oil, and combinations thereof.

Examples of antipsoriatic agents include, but are not limited to,corticosteroids (e.g., betamethasone dipropionate, betamethasonevalerate, clobetasol propionate, diflorasone diacetate, halobetasolpropionate, triamcinonide, dexamethasone, fluocinonide, fluocinoloneacetonide, halcinonide, triamcinolone acetate, hydrocortisone,hydrocortisone venerate, hydrocortisone butyrate, aclometasonedipropionte, flurandrenolide, mometasone furoate, and methylprednisoloneacetate), methotrexate, cyclosporine, calcipotriene, anthraline, shaleoil, elubiol, ketoconazole, coal tar, salicylic acid, zinc pyrithione,selenium sulfide, hydrocortisone, sulfur,2,2′-sulfanediylbis(4,6-dichlorophenol) (bithionol),6-hydroxy-1,3-benzoxathiol-2-one (tioxolone), 2,7-dimethylthianthrene(mesulfen), menthol, and pramoxine hydrochloride, and combinationsthereof.

Examples of anti-viral agents include, but are not limited to,imiquimod, podofilox, podophyllin, interferon alpha, acyclovir,famcyclovir, valcyclovir, reticulos and cidofovir.

Anti-seborrea or sebum inhibition agents such as elubiol.

Examples of anti-dandruff agents include but are not limited to zincpyrithione, elubiol, coal tar, salicylic acid or selenium sulfide,sulphur, ketoconazole, corticosteroids such as fluocinolone acetonide,caffeine and combinations thereof.

Active agents for treating keratosis pilaris. Examples of active agentsfor treating keratosis pilaris include but are not limited to fluoracil,Imiquimod, aminolevulinic acid and combinations thereof.

Examples of anti-inflammatory agents, include, but are not limited to,non-steroidal and steroidal anti-inflammatory agents such ascorticosteroids such as hydrocortisone, hydroxyltriamcinolonealphamethyl dexamethasone, dexamethasone-phosphate, beclomethasonedipropionate, clobetasol valerate, desonide, desoxymethasone,desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasonediacetate, diflucortolone valerate, fluadrenolone, fluclaroloneacetonide, fludrocortisone, flumethasone pivalate, fluosinoloneacetonide, fluocinonide, flucortine butylester, fluocortolone,fluprednidene (fluprednylidene)acetate, flurandrenolone, halcinonide,hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone,triamcinolone acetonide, cortisone, cortodoxone, flucetonide,fludrocortisone, difluorosone diacetate, fluradrenalone acetonide,medrysone, amciafel, amcinafide, betamethasone, chlorprednisone,chlorprednisone acetate, clocortelone, clescinolone, dichlorisone,difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone,fluprednisolone, hydrocortisone valerate, hydrocortisonecyclopentylproprionate, hydrocortamate, meprednisone, paramethasone,prednisolone, prednisone, beclomethasone dipropionate, betamethasonedipropionate, and triamcinolone, and combinations thereof. Examples ofnon-steroidal anti-inflammatory agents include but not limited to COXinhibitors, LOX inhibitors, and p38 kinase inhibitors, immunosuppresantagents such as cyclosporin, and cytokine synthesis inhibitors. Othernatural anti-inflammatories include, but are not limited to, extracts offeverfew, boswellia, aloe vera, chamomille, lavender, soy, or oats,beta-glucan, and totarol. Other active agents include, but are notlimited to, wound healing enhancing agents such as calcium alginate,collagen, recombinant human platelet-derived growth factor (PDGF) andother growth factors, ketanserin, iloprost, prostaglandin E₁ andhyaluronic acid (including cross-linked hyaluronic acid); scar reducingagents such as mannose-6-phosphate; analgesic agents; debriding agentssuch as papain, and enzymatic debriding agents; and anesthetics such aslidocaine and benzocaine. In one embodiment, the composition comprisesone or more of menthol, camphor, an antihistamine, or a local anestheticsuch as tetracaine, lidocaine, prilocaine, benzocaine, bupivacaine,mepivacaine, dibucaine, etidocaine, butacaine, cyclomethycaine,hexylcaine, proparacaine, and lopivacaine, capsaicin, or oatmeal.

Examples of vasodilators include: methylnicotinate, arginine,hexylnicotinate, papaverine, tolazoline, acetylcholine, sodiumnitroprusside, nitroglycerine, adensosine or a combination thereof.

Examples of suitable UV absorbers include benzophenone, bornelone, butylpaba, cinnamidopropyl trimethyl ammonium chloride, disodiumdistyrylbiphenyl disulfonate, paba, potassium methoxycinnamate, andmixtures thereof.

Examples of anti-cancer agents include: AG-490; aldesleukin;alemtuzumab; alitretinoin; allopurinol; altretamine; amifostine; An-238;anastrozole; arsenic trioxide; asparaginase; BCG Live (BacillusCalmette-Guerin); bevazizumab; bexarotene; bleomycin; busulfan;calusterone; capecitabine; capecitabine; carboplatin; carmustine;celecoxib; cetuximab; chlorambucil; cisplatin; cladribine;cyclophosphamide; cyclophosphamide; cytarabine; dactinomycin;darbepoetin alfa; dasatinib; daunorubicin; daunorubicin, daunomycin;denileukin diftitox; dexrazoxane; docetaxel; doxorubicin; dromostanolonepropionate; Elliott's B Solution; endostatin; epirubicin; epoetin alfa;estramustine; etoposide phosphate; etoposide, VP-16; exemestane;filgrastim; floxuridine; fludarabine; fluorouracil; FTI-2777;fulvestrant; gefitinib; gemcitabine; gemcitabine; gemtuzumab ozogamicin;GGTI-298; goserelin acetate; gossypol; hydroxyurea; ibritumomab;idarubicin; idarubicin; ifosfamide; imatinib mesylate; interferonalfa-2a; interferon alfa-2b; IL-2; IL-12; irinotecan; letrozole;leucovorin; levamisole; lomustine; meclorethamine; nitrogen mustard;megestrol acetate; melphalan, L-PAM; mercaptopurine, 6-MP; mesna;methotrexate; methoxsalen; mitomycin C; mitotane; mitoxantrone;nandrolone phenpropionate; nofetumomab; oprelvekin; oxaliplatin;paclitaxel; pamidronate; pegademase; pegaspargase; pegfilgrastim;pentostatin; pentostatin; pipobroman; plicamycin; mithramycin; porfimersodium; PP2; procarbazine; quinacrine; rasburicase; RC3095; rituximab;sargramostim; streptozocin; talc; tamoxifen; temozolomide; teniposide,VM-26; testolactone; thioguanine, 6-TG; thiotepa; topotecan; toremifene;tositumomab; trastuzumab; tretinoin, ATRA; UO126; uracil mustard;valrubicin; vinblastine; vincristine; vinorelbine; wortmanin; andzoledronate.

In certain embodiments, the active are water soluble actives. Suitableexamples include, but are not limited to, sulfonated molecules such as,for example sodium sulfate, water soluble vitamins (or theirderivatives) such as thiamine, riboflavin (B2), nicotinic acid, niacin,biotin (B7), folate (B9), cobalamin, panthenol, panththenic acid,choline, ascorbic acid; water soluble proteins such as keratins,collagens, elastins, wheat germ proteins, wheat proteins, soy proteins,protease, serum proteins, hair proteins; water soluble peptides andpolypeptides such as amino acids derived from protein hydrolysis such asthose described in U.S. Pat. No. 6,419,913, herein incorporated byreference; plant extracts obtained from water extract process such asfeverfew extracts and soy extracts; ethanol soluble such actives includedepilating agents such as calcium thioglycolate, potassium thioglycolateand external analgesics and local anesthetics such as benzocaine.

In certain embodiments, the active is oil soluble. Suitable examplesinclude, but are not limited to, vitamins or their derivatives such asvitamin E, vitamin D₃, vitamin A, retinol, retinoids or melatonin.

Mixtures of the above additional actives can also be used.

Some embodiments of the present invention further include colorstabilizers. Suitable color stabilizers include, but are not limited to,butylated hydroxytoluene or IRGANOX® 1010, a hindered phenol availablefrom Ciba-Geigy, Hawthorne, N.Y., U.S. A. IRGANOX® 1010 is tetraki s [methyl ene(3, 5-di-tert-butyl-4-hydroxyhydrocinnamate)] methane. Incertain embodiments, the color stabilizer is used in an amount of about0.05 to about 1.0% by weight based on the total weight of thecompositions of the present invention.

Non-Ionic Lipid

In certain embodiments, the compositions of the present inventionfurther include a non-ionic lipid. The non-ionic lipid can form micro-or nano- vesicles in an emulsion of any types such as oil in water(o/w), water in oil (w/o), oil in water in silicone.

In certain embodiments, the non-ionic lipids include non-ionic lipidsuch as glyceryl monoesters having a fatty acid chain containing fromabout 3 to about 50 carbon atoms, and optionally from about 10 to about18 carbon atoms; glyceryl diesters having a fatty acid chain containingfrom about 5 carbon atoms to about 25 carbon atoms, and optionally fromabout 10 carbon atoms to about 18 carbon atoms; alkoxylated alcohols;alkoxylated alkyl phenols; alkoxylated acids; alkoxylated amides;alkoxylated sugar derivatives; alkoxylated derivatives of natural oilsor waxes; polyoxyethylene polyoxypropylene block copolymers;polyoxyethylene ether fatty acids having a fatty acid chain containingfrom about 10 carbon atoms to about 18 carbon atoms; steroids; fattyacid esters of alcohols where the fatty acid is straight or branchedchain having from about 10 carbon atoms to about 20 carbon atoms and thealcohol is straight or branched chain having 1 to 10 carbon atoms; andmixtures thereof, wherein, optionally, the alkoxylated lipids arealkoxylated with ethylene oxide or propylene oxide, or optionallyethylene oxide.

Non-limiting examples of suitable glyceryl monoesters include, but arenot limited to, glyceryl caprate, glyceryl caprylate, glyceryl cocate,glyceryl erucate, glyceryl hydroxysterate, glyceryl isostearate,glyceryl lanolate, glyceryl laurate, glyceryl linolate, glycerylmyristate, glyceryl oleate, glyceryl PABA, glyceryl palmitate, glycerylricinoleate, glyceryl stearate, glyceryl thiglycolate, and mixturesthereof, optionally glyceryl laurate, glyceryl myristate and mixturesthereof.

Non-limiting examples of suitable glyceryl diesters include, but are notlimited to, glyceryl dilaurate, glyceryl dioleate, glyceryl dimyristate,glyceryl disterate, glyceryl sesuioleate, glyceryl stearate lactate, andmixtures thereof, optionally glyceryl dilaurate, glyceryl dimyristateand mixtures thereof.

Non-limiting examples of suitable polyoxyethylene fatty ethers include,but are not limited to, polyoxyethylene cetyl/stearyl ether,polyoxyethylene cholesterol ether, polyoxyethylene laurate or dilaurate,polyoxyethylene stearate or distearate, polyoxyethylene lauryl orstearyl ether, and mixtures thereof, wherein the polyoxyethylene headgroup ranges from about 2 to about 100 groups. In certain embodiments,the polyoxyethylene fatty ethers include polyoxyethylene stearyl ether,polyoxyethylene myristyl ether, polyoxyethylene lauryl ether having fromabout 3 to about 10 oxyethylene units and mixtures thereof.

Non-limiting examples of suitable steroids include, but are not limitedto, cholesterol, betasitosterol, bisabolol, and mixtures thereof.

Non-limiting examples of suitable fatty acid esters of alcohols includeisopropyl myristate, aliphati-isopropyl n-butyrate, isopropyln-hexanoate, isopropyl n-decanoate, isoproppyl palmitate, octyidodecylmyristate and mixtures thereof.

In certain embodiments, the non-ionic lipid in the compositions of theinvention have the structure shown in formula I below:

R₅—(OCH₂CH₂)y-OH   Formula I

wherein R₅ is a branched or unbranched alkyl group having from about 6to about 22 carbon atoms and y is between about 4 and about 100, andpreferably, between about 10 and about 100. A preferred alkoxylatedalcohol is the species wherein R₅ is a lauryl group and y has an averagevalue of 23, which is known by the CTFA name “laureth 23” and isavailable from ICI Americas, Inc. of Wilmington, Del. under thetradename, “BRIJ 35.”

In other embodiments, the alkoxylated alcohol is an ethoxylatedderivative of lanolin alcohol. Lanolin alcohol is a mixture of organicalcohols obtained from the hydrolysis of lanolin. An example of anethoxylated derivative of lanolin alcohol is laneth-10, which is thepolyethylene glycol ether of lanolin alcohol with an averageethoxylation value of 10.

In an embodiment, the alkoxylated alcohol is polyoxypropylenepolyoxyethylene alkyl ether, the structure of which is shownschematically in formula II below:

wherein x:q is about 2:2 to about 38:37. An exemplary member of thisclass of materials is the material known by the CTFA name“PPG-12-Buteth-16,” which conforms to structure II above wherein R is abutyl group, x has an average value of 12 and y has an average value of16. This material is available from Amerchol Corp. of Edison, N.J. underthe tradena me, “UCON Fluid 50-HB-660.”

Another type of non-ionic lipids include alkoxylated alkyl phenols,which generally conform to the structure of formula III:

wherein R₆ is a branched or unbranched alkyl group having about 6 toabout 22 carbon atoms and z is between about 7 and 120, and preferably,between about 10 and about 120. An especially preferred member of thisclass of materials is the species wherein R₆ is a nonyl group and z hasan average value of about 14. This material is known by the CTFA name“nonoxynol-14” and is available under the tradename, “MAKON 14” from theStepan Company of Northfield, Ill.

Another type of non-ionic lipids include alkoxylated acids, which areesters of an acid, most usually a fatty acid, with a polyalkyleneglycol. An exemplary material of this class has the CTFA name “PEG-8laurate,” and the following structure shown in formula IV.:

Another type of non-ionic lipids includes the alkoxylated amides thatmay conform to one or both of structures V or VI shown below:

wherein n is from about 8 to about 100 and the sum of m plus b is fromabout 8 to about 100. An exemplary member of this class is known by theCTFA name “PEG-6 Cocoamide,” which conforms generally to structure Vwherein R′CO represents the fatty acids derived from coconut oil and nhas an average value of about 6.

Another type of non-ionic lipids includes the alkoxylated sugarderivatives. An exemplary member of this class, which is known by theCTFA name “Polysorbate 20,” is a mixture of laurate esters of sorbitoland sorbitol anhydrides, consisting predominately of the monoester,condensed with about 20 moles of ethylene oxide. This material isavailable under the tradename “TWEEN 20” from ICI Americas ofWilmington, Del.

Another example of an alkoxylated sugar derivative useful in thecompositions of the invention is PEG-20 methylglucose sesquistearate,which is the polyethyleneglycol ether of the sesquiester of methylglucose and stearic acid, contains an average of 20 moles of ethyleneoxide, and is available under the tradename, “Glucamate SSE-20” from theAmerchol Corp. of Edison, N.J.

Another type of non-ionic lipids includes the alkoxylated derivatives ofnatural oils and waxes. Examples of this class of material includePEG-40 lanolin, PEG-40 castor oil and PEG-40 hydrogenated castor oil.

Another type of non-ionic lipids includes polyoxyethylenepolyoxypropylene block copolymers. These materials are generally knownby the CTFA name, “Poloxamer” and conform to the structure VII.:

wherein a:d:e is from about 2:16:2 to about 98:67:98. Exemplary membersof this class of materials useful in the compositions of the inventionare “Poloxamer 101” and “Poloxamer 182,” in which a, d, and e haveaverage values of 2, 16 and 2 and 8, 30 and 8, respectively.

In certain embodiments, the non-ionic lipids include polyoxyethyleneC₄-C₂₆ fatty ethers, glyceryl diesters, and mixtures thereof.Optionally, non-ionic lipids include polyoxyethylene C₁₀-C₁₈ fattyethers such as polyoxyethylene stearyl ether (steareth-10),polyoxyethylene myristyl ether, and polyoxyethylene lauryl ether,glyceryl dilaurate, glyceryl dimystate, glyceryl distearate, andmixtures thereof, wherein, optionally, each ether has from about 5 toabout 10 oxyethylene units. Optionally, non-ionic lipid is apolyoxyethylene stearyl ether (steareth-10).

In certain embodiments, the non-ionic lipid is present in thecomposition in an amount from about 0.1% to about 20%, optionally, fromabout 0.2% to about 15%, or, optionally, from about 0.5% to about 10%,by weight of the composition.

When present, the concentration of the polyoxyethylene C₄-C₂₆ fattyether is from about 0.1% to about 15%, optionally, from about 0.2% toabout 10%, or, optionally, from about 0.3% to about 5%, by weight of thecomposition.

The Admixture

In certain embodiments, the compositions of the present inventionfurther include an admixture comprising: 1) an acid selected from thegroup consisting of intermediates of the Kreb cycle, non-Kreb cycleintermediate alpha keto acid, derivatives thereof and mixtures thereof;and/or 2) an antioxidant and 3) a mixture of saturated and unsaturatedfatty acids or a source of of such mixture of saturated and unsaturatedfatty acids.

In certain embodiments, the admixture is present in the composition at aconcentration of from 0.1% (or about 0.1%) to 20% (or about 20%),optionally from 0.1% (or about 0.1%) to 30% (or about 30%), optionallyfrom 0.5% (or about 0.5%) to 20% (or about 20%), or optionally from 0.5%(or about 0.5%) to 10% (or about 10%), by weight, of the admixture.

Acid Component of Admixture

In certain embodiments, the acid component of the admixture of thepresent invention is selected from the group consisting of intermediatesof the Kreb cycle, non-Kreb cycle alpha keto acids, derivatives thereofand mixtures thereof.

Kreb cycle (or Citric acid cycle) intermediates useful herein, include,but are not limited to, 2-oxoglutarate, fumarate, succinate,oxaloacetate, citrate, cis-aconitate, isocitrate, oxalosuccinate,alpha-ketoglutarate, L-malate, esters thereof, ethers thereof or saltsthereof and mixtures thereof.

In other embodiments, the acid component is a non-Kreb cycleintermediate alpha-keto acid (or 2-oxoacid). The alpha-keto acid (or2-oxoacid) has the keto group adjacent to the carboxylic acid. By“non-Kreb cycle intermediate”, as used herein, means a chemical,compound or intermediate not produced by the Kreb cycle or Citric Acidcycle. In certain embodiments, suitable non-Kreb cycle alpha-keto acidsinclude, but are not limited to, pyruvic acid (alpha-ketopropionicacid), alpha-ketoisovaleric acid, alpha-ketoisocaproic acid, saltsthereof and mixtures thereof. It should be understood, however, that inaddition to these alpha-keto acids, the unqualified term “alpha-ketoacids” further includes, but is not limited to, alpha ketoglutaric acid.

In certain embodiments, the alpha-keto acid useful as the acid componentis a pyruvic acid. Pyruvic acid suitable for use in the presentinvention may be selected from the group consisting of pyruvic acid,salts of pyruvic acid, prodrugs of pyruvic acid, and mixtures thereof.In certain embodiments, the salts of pyruvic acid may be alkali saltsand alkaline earth salts. In certain embodiments, the pyruvic acid isselected from the group consisting of pyruvic acid, lithium pyruvate,sodium pyruvate, potassium pyruvate, magnesium pyruvate, calciumpyruvate, zinc pyruvate, manganese pyruvate, methyl pyruvate, andmixtures thereof.

In other embodiments, the pyruvic acid is selected from the group ofsalts consisting of sodium pyruvate, potassium pyruvate, magnesiumpyruvate, calcium pyruvate, zinc pyruvate, manganese pyruvate, and thelike, and mixtures thereof In still other embodiments, the pyruvic acidis sodium pyruvate.

Without being limited by theory, it is believed that the acid componentacts as the energy source component for the admixture. In certainembodiments, the acid is present in the composition in an amount of from0.01% (or about 0.01%) to 99.98% (or about 99.98%), or optionally 10%(or about 10%) to 90% (or about 90%), or optionally from 20% (or about20%) to 70% (or about 70%), or optionally from 25% (or about 25%) to 50%(or about 50%), or optionally from 30% (or about 30%) to 40% (or about40%), or optionally about 33%, by weight, of the admixture.

Antioxidant Component of the Admixture

Antioxidants, as mentioned above, are also present as a component of theadmixture of the present invention. Generally, antioxidants aresubstances which inhibit oxidation or suppress reactions promoted byoxygen or peroxides. Without being limited by theory, it is believedthat antioxidants, or, optionally, lipid-soluble antioxidants, can beabsorbed into the cellular membrane to neutralize oxygen radicals andthereby protect the hair follicles from oxidative damage. In certainembodiments, the antioxident component may be selected from the groupconsisting of all forms of Vitamin A including lycopene, lutein, retinaland 3,4-didehydroretinal, all forms of carotene such as alpha-carotene,beta-carotene (beta, beta-carotene), gamma-carotene, delta-carotene, allforms of Vitamin C (D-ascorbic acid, L-aseorbic acid), all forms oftocopherol such as Vitamin E (alpha-tocopherol,3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltri-decyl)-2H-1-benzopyran-6-ol), beta-tocopherol, gamma-tocopherol, delta-tocopherol,tocoquinone, tocotrienol, and Vitamin E esters which readily undergohydrolysis to Vitamin E such as Vitamin E acetate and Vitamin Esuccinate, and Vitamin E salts such as Vitamin E phosphate, prodrugs ofVitamin A, carotene, Vitamin C, and Vitamin E, salts of Vitamin A,carotene, Vitamin C, and Vitamin E, and the like, flavonoids andmixtures thereof. Flavonoids useful in the present can be found in U.S.Pat. No. 6,051,602 to Bissett, herein incorporated by reference. Inother embodiments, the antioxidant is selected from the group oflipid-soluble antioxidants consisting of Vitamin A, beta-carotene,tocopherol, and mixtures thereof. In still other embodiments, theantioxidant is tocopherol Vitamin E or Vitamin E acetate. In yet otherembodiments, the antioxidant is a polyphenol such as resveratrol orepigallocatechin gallate.

In certain embodiments, the antioxidant component is present in thecomposition in an amount of from 0.01% (or about 0.01%) to 99.98% (orabout 99.98%), or optionally 10% (or about 10%) to 90% (or about 90%),or optionally from 20% (or about 20%) to 70% (or about 70%), oroptionally from 25% (or about 25%) to 50% (or about 50%), or optionallyfrom 30% (or about 30%) to 40% (or about 40%), or optionally about 33%,by weight, of the admixture.

The Fatty Acid Mixture Component or Fatty Acid Mixture Source Componentof the Admixture

The admixture of the present invention also contains as a componentthereof a mixture of saturated and unsaturated fatty acids, free orbound, or a source of such saturated and unsaturated fatty acids usefulin providing a readily available source of nutrients to hair follicles

Suitable mixtures of saturated and unsaturated fatty acids may bederived from animal and vegetable fats and waxes, mammalian or fish eggmaterials, prodrugs of saturated and unsaturated fatty acids useful inthe present compositions, and mixtures thereof. The fatty acids in thefatty acid mixture may be in the form of mono-, di-, or trigylcerides,or free fatty acids, or mixtures thereof.

In one embodiment, the fatty acid mixture of saturated and unsaturatedfatty acids has a composition similar to that of human fat and comprisesthe following fatty acids: butyric acid, caproic acid, caprylic acid,capric acid, lauric acid, myristic acid, myristoleic acid, palmiticacid, palmitoleic acid, stearic acid, oleic acid, linoleic acid,linolenic acid, arachidic acid, dihomolinoleic acid, arachidonic acid,behenic acid, lignoceric acid and gadoleic acid. Typically, butyricacid, caproic acid, caprylic acid, capric acid, lauric acid, myristicacid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid,oleic acid, linoleic acid, linolenic acid, arachidic acid, and gadoleicacid are present in the mixture in about the following percentages byweight, respectively: about 0.2%-0.4% butyric acid, about 0.1% caproicacid, about 0.3%-0.8% caprylic acid, about 2.2%-3.5% capric acid, about0.9%-5.5% lauric acid, about 2.8%-8.5% myristic acid, about 0.1%-0.6%myristoleic acid, about 23.2%-24.6% palmitic acid, about 1.8%-3.0%palmitoleic acid, about 6.9%-9.9% stearic acid, about 36.0%-36.5% oleicacid, about 20%-20.6% linoleic acid, about 7.5-7.8% linolenic acid,about 1.1%-4.9% arachidic acid, about 2%-3% dihomolinoleic acid, about7%-9% arachidonic acid, about 3%-4% behenic acid, about 11%-13%lignoceric acid and about 3.3%-6.4% gadoleic acid.

In another embodiment, the fatty acid mixture of saturated andunsaturated fatty acids has a composition similar to chicken fat andcomprising the following fatty acids: lauric acid, myristic acid,myristoleic acid, pentadecanoic acid, palmitic acid, palmitoleic acid,margaric acid, margaroleic acid, stearic acid, oleic acid, linoleicacid, linolenic acid, arachidic acid, and gadoleic acid. Optionally,lauric acid, myristic acid, myristoleic acid, pentadecanoic acid,palmitic acid, palmitoleic acid, margaric acid, margaroleic acid,stearic, oleic acid, linoleic acid, linolenic acid, arachidic acid, andgadoleic acid are present in the mixture in about the followingpercentages by weight, respectively: about 0.1% lauric acid, about 0.8%myristic acid, about 0.2% myristoleic acid, about 0.1% pentadecanoicacid, about 25.3% palmitic acid, about 7.2% palmitoleic acid, about 0.1%magaric acid, about 0.1% heptadecenoic acid, about 6.5% stearic acid,about 37.7% oleic acid, about 20.6% linoleic acid, about 0.8% linolenicacid, about 0.2% arachidic acid, and about 0.3% gadoleic acid.

In certain other embodiments, the fatty acid mixture of saturated andunsaturated fatty acids has a composition similar to lecithin. Lecithin(phosphatidylcholine) is a phosphatide found in all living organisms(plants and animals) and is a significant constituent of nervous tissueand brain substance. Lecithin is a mixture of the diglycerides ofstearic acid, palmitic acid, and oleic acid, linked to the choline esterof phosphoric acid. The product of commerce is predominantly soybeanlecithin obtained as a by-product in the manufacturing of soybean oil.Soybean lecithin contains by weight palmitic acid 11.7%, stearic acid4.0%, palmitoleic acid 8.6%, oleic acid 9.8%, linoleic acid 55.0%,linolenic acid 4.0%, C₂₀ to C₂₂ acids (includes arachidonic acid) 5.5%.Lecithin may be represented by the formula: C₈H₁₇O₅NR⁹R¹⁰ wherein eachof R⁹ and R¹⁰ are, independently, selected from the group consisting ofstearic acid, palmitic acid, and oleic acid.

In certain other embodiments, the fatty acid mixture of saturated andunsaturated fatty acids has a composition similar to egg yolk. Thecomposition (by weight) of the most prevalent fatty acid mixture in eggyolk can be broken into by weight:

-   -   A. unsaturated fatty acids such as oleic acid (about 47%),        linoleic acid (about 16%), palmitoleic acid (about 5%), and        linolenic acid (about 2%); and    -   B. saturated fatty acids: such as palmitic acid (about 23%),        stearic acid (about 4%), and myristic acid (about 1%).

Egg yolk is also a source of lecithin.

The above fatty acid mixtures (or fatty acid mixture sources) andpercentages of fatty acids present in the various fatty acid mixture (orsources thereof) are provided as examples. The exact type of fatty acidpresent in the fatty acid mixture (or mixture sources) and the exactamount of fatty acid employed in the fatty acid mixture (or mixturesources) may be varied in order to obtain the result desired in thefinal product and such variations are now within the capabilities ofthose skilled in the art without the need for undue experimentation.

In certain embodiments of the present invention, the fatty acid mixtureor fatty acid mixture source comprising at least 7, optionally at least14, and optionally at least 22, unsaturated or saturated fatty acidsselected from the group consisting of, but not limited to, butyric acid,caproic acid, caprylic acid, capric acid, lauric acid, myristic acid,myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleicacid, linoleic acid, linolenic acid, arachidic acid, gadoleic acid,pentadecanoic acid, margaric acid, margaroleic acid, behenic acid,dihomolinoleic acid, arachidonic acid and lignoceric acid. Other usefulfatty acids can be found in U.S. Pat. No. 4,874,794 to Adachi et al.,herein incorporated by reference.

In certain embodiments, the fatty acid mixture in the admixture isobtained or sourced from oil mixtures. For example, cottonseed oil has a2:1 ratio of polyunsaturated to saturated fatty acids. Its fatty acidprofile generally consists of 70% unsaturated fatty acids including 18%monounsaturated (oleic), 52% polyunsaturated (linoleic) and 26%saturated (primarily palmitic and stearic). More specifically,cottonseed oil has fatty acids present in the mixture in about thefollowing percentages by weight, respectively: about 0.5-2.0% myristicacid, about 17.0-29.0% palmitic acid, less than about 1.5% palmitoleicacid, about 1.0-4.0% stearic acid, about 13.0-44.0% oleic acid, about40.0-63.0% linoleic acid, and about 0.1-2.1% linolenic acid.

Cocoa butter has fatty acids present in a mixture at about the followingpercentages by weight, respectively: at least about 0.1% myristic acid,about 0.5-26.3% palmitic acid, at least about 0.4% palmitoleic acid,about 0.5-33.8% stearic acid, about 0.5-34.4% oleic acid, and about0.5-3.1% linoleic acid.

Olive oil was determined in one study to have fatty acids present in amixture at about the following percentages by weight, respectively:about 0.5-9.0% palmitic acid, at least about 0.4% palmitoleic acid,about 0.5-2.7% of stearic acid, about 0.5-80.3% oleic acid, about0.5-6.3% of linoleic acid, and about 0.5-0.7% linolenic acid.

Oils suitable for use as a fatty acid mixture source include, but arenot limited to, Adansonla digitata oil; apricot (Prunus armeniaca)kernel oil; Argania spinosa oil; Argemone mexicana oil; avocado (Perseagratissima) oil; babassu (Orbignya olelfera) oil; balm mint (Melissaofficinalis) seed oil; bitter almond (Prunus amygdalus amara) oil;bitter cherry (Prunus cerasus) oil; black currant (Ribes nigrum) oil;borage (Borago officinalis) seed oil; brazil (Bertholletia excelsa) nutoil; burdock (Arctium lappa) seed oil; butter; calophyllum tacamahacaoil; camellia kissi oil; camellia oleifera seed oil; canola oil; caraway(Carum carvi) seed oil; carrot (Daucus carota sativa) oil; cashew(Anacardium occidentale) nut oil; castor oil benzoate; castor (Ricinuscommunis) oil; cephalins; chaulmoogra (Taraktogenos kurzii) oil, chia(Salvia hispanica) oil; cocoa (Theobrama cocao) butter; coconut (Cocosnucifera) oil; cod liver oil; coffee (Coffea arabica) oil; corn (Zeamays) germ oil; corn (Zea mays) oil; cottonseed (Gossypium) oil;cucumber (Cucumis sativus) oil; dog rose (Rosa canina) hips oil; eggoil; emu oil; epoxidized soybean oil; evening primrose (Oenotherabiennis) oil; fish liver oil; gevuina avellana oil; goat butter; grape(Vitis vinifera) seed oil; hazel (Croylus americana) nut oil; hazel(Corylus aveilana) nut oil; human placental lipids; hybrid safflower(Carthamus tinctorius) oil; hybrid sunflower (Helianthus annuus) seedoil; isatis tinctoria oil; job's tears (Coix lacryma-jobi) oil; jojobaoil; kiwi (Actinidia chinensis) seed oil; kukui (Aleurites moluccana)nut oil; lard; linseed (Linum usitatissiumum) oil; lupin (Lupinus albus)oil; macadamia nut oil; macadamia ternifolia seed oil; macadamiaintegrifolia seed oil; maleated soybean oil; mango (Mangifera indica)seed oil; marmot oil; meadowfoam (Limnanthes fragraalba) seed oil;menhaden oil; milk lipids; mink oil; moringa pterygosperma oil;mortierella oil; musk rose (Rosa moschata) seed oil; neatsfoot oil; neem(Melia azadirachta) seed oil; oat (Avena sativa) kernel oil; olive (Oleaeuropaea) husk oil; olive (Olea europaea) oil; omental lipids; orangeroughy oil; ostrich oil; oxidized corn oil; palm (Elaeis guineensis)kernel oil; palm (Elaeis guineensis) oil; passionflower (Passifloraedulis) oil; peach (Prunus persica) kernel oil; peanut (Arachishypogaea) oil; pecan (Caiya illinoensis) oil; pengawar djambi (Cibotiumbarometz) oil; pistachio (Pistacia vera) nut oil; placental lipids;poppy (Papaver orientale) oil; pumpkin (Cucurbita pepo) seed oil; quinoa(Chenopodium quinoa) oil; rapeseed (Brassica campestris) oil; rice(Oryza sativa) bran oil; rice (Oryza sativa) germ oil; safflower(Carthamus tinctorius) oil; salmon oil; sandalwood (Santalum album) seedoil; seabuchthorn (Hippophae rhamnoides) oil; sesame (Sesamum indicum)oil; shark liver oil; shea butter (Butyrospermum parkii); silk wormlipids; skin lipids; soybean (Glycine soja) oil; soybean lipid;Sphingolipids; sunflower (Helianthus annuus) seed oil; sweet almond(Prunus amygdalus dulcis) oil; sweet cherry (Prunus avium) pit oil; talioil; tallow; tea tree (Melaleuca alternifolia) oil; telphairia pedataoil; tomato (Solanum lycopersicum) oil; trichodesma zeylanicum oil; tunaoil; vegetable oil; walnut (Juglans regia) oil; wheat bran lipids; andwheat (Triticum vulgare) germ oil and mixtures thereof.

In certain embodiments, the oil is present in the compositions of thepresent invention in a total amount of from 0.01% (or about 0.01%) to99.98% (or about 99.98%), or optionally 10% (or about 10%) to 90% (orabout 90%), or optionally from 20% (or about 20%) to 70% (or about 70%),or optionally from 25% (or about 25%) to 50% (or about 50%), oroptionally from 30% (or about 30%) to 40% (or about 40%), or optionallyabout 33%, by weight of the admixture.

In certain embodiments the oil mixture used as a source of the fattyacid mixture is formed from oils selected to provide the following fattyacid composition: 0.3% (or about 0.3%) myristic acid, 19% (or about 19%)palmitic acid, 0.5% (or about 0.5%) palmitoleic acid, 13% (or about 13%)stearic acid, 44.4% (or about 44.4%) oleic acid, 21.3% (or about 21.3%)linoleic acid, and 0.5% (or about 0.5%) linolenic acid. In certainembodiments the oil mixture used as a source of the fatty acid mixtureis formed from oils selected from the group consisting of cocoa butter,olive oil, cottonseed oil and mixtures thereof.

In certain embodiments, the fatty acid mixture or source of the fattyacid mixture is present in the compositions of the present invention inan amount from 0.01% (or about 0.01%) to 99.98% (or about 99.98%), oroptionally 10% (or about 10%) to 90% (or about 90%), or optionally from20% (or about 20%) to 70% (or about 70%), or optionally from 25% (orabout 25%) to 50% (or about 50%), or optionally from 30% (or about 30%)to 40% (or about 40%), or optionally about 33%, by weight of theadmixture.

In certain embodiments, the ratio of the acid component to the fattyacid mixture component on a weight/weight basis is from 0.01:1 (or about0.01:1) to 1:0.01 (or about 1:0.01), optionally from 1:1 (or about 1:1)to 1:0.1 (or about 1:0.1), optionally from 1:1 (or about 1:1) to 1:0.5(or about 1:0.5), or optionally, 1:1 (or about 1:1).

In certain embodiments, the ratio of the fatty acid mixture component tothe antioxidant component on a weight/weight basis is from 0.01:1 (orabout 0.01:1) to 1:0.01 (or about 1:0.01), optionally from 1:1 (or about1:1) to 1:0.1 (or about 1:0.1), optionally from 1:1 (or about 1:1) to1:0.5 (or about 1:0.5).

In certain embodiments, the ratio of the pyruvic acid component or thefatty acid mixture component to the antioxidant component on aweight/weight basis is from 1:1 (or about 1:1) to 1:0.01 (or about1:0.01).

Other Materials:

Various other materials may also be present in the compositions usefulin the subject invention. These include humectants, proteins andpolypeptides, preservatives, an alkaline agent and mixtures thereof. Thecompositions of the present invention may also comprise chelating agents(e.g., EDTA, citric acid, phytic acid) and preservatives (e.g.,parabens). In addition, the topical compositions useful herein cancontain conventional cosmetic adjuvants, such as dyes, sunscreen (e.g.,titanium dioxide), pigments, and fragrances. A more detailed discussionof these and other materials can be found in previously incorporatedU.S. Patent Publication 2008/0145331 to Bruning et al. as well as inU.S. Pat. No. 5,658,956 to Martin et al., which patent is hereinincorporated by reference in its entirety.

Mixtures of the above preservatives can also be used.

In certain embodiments, the compositions of the present invention havean apparent pH of from 4.0 (or about 4.0) to 7.0 (or about 7.0),optionally from 4.0 (or about 4.0) to 6.0 (or about 6.0), optionallyfrom 4.5 (or about 4.5) to 5.5 (or about 5.5). In certain rinse off orwash off embodiments, the compositions of the present invention have anapparent pH of from 3.0 (or about 3.0) to 8.0 (or about 8.0), optionallyfrom 4.0 (or about 4.0) to 6.0 (or about 6.0),

Methods of Use

The use of compositions of this invention for accelerating the onset ofthe anagen phase of hair growth in a mammal and/or increasing the rateat which terminal hair appears on the skin by topical application of thepresent compositions was determined by the mice studies described below.

In certain embodiments, the compositions of this invention should beapplied topically to the desired area of the mammalian or human body atleast once per day for at least 11 weeks, optionally at least 9 weeks,or optionally at least 7 weeks. The hair growth benefits of the presentinvention may be maintained indefinitely by chronic administration ofthe compositions of the present invention.

EXAMPLES

The compositions of the present invention as described in followingexamples illustrate specific embodiments of compositions of the presentinvention, but are not intended to be limiting thereof. Othermodifications can be undertaken by the skilled artisan without departingfrom the spirit and scope of this invention.

Example 1

Treatment formulation #1 (Table 1) is prepared as described below usingconventional mixing technology.

TABLE 1 Treatment formulation # 1 Inventive Treatment Formulation # 1Ingredient % (wt/wt) Ethanol 20.00 Pentylene glycol¹ 4.00 Glycerin 12.00Lactic acid 3.20 Minoxidil 5.07 Butylated 0.10 hydroxytoluene (BHT)Water 45.13 Cetyl lactate⁴ 3.00 Sodium Pyruvate 1.00 Tocopheryl Acetate0.50 Steareth-10³ 1.50 Steareth-2³ 2.00 Polyquaternium 37² 1.50 Total100.00 Apparent pH 4.6 Viscosity⁵ 9500 cps ¹Hydrolite 5 supplied bySymrise, Teterboro, NJ ²Cosmedia Ultra 300 supplied by BASF, FlorhamPark, NJ ³supplied by Croda, Edison, NJ ⁴supplied by Ashland Inc.,Covington, KY ⁵measured using a Brookfield RV (spindle 4, speed 6 RPM at1 minute following the temperature equilibrated at 25° C. ± 1° C.)

The Treatment formulation #1 is prepared according to the followingprocedure:

-   (1) The ethanol is added to a suitably sized first beaker equipped    with an overhead mixer.-   (2) The pentylene glycol, glycerin, citric acid (if applicable) and    lactic acid are added to the beaker and the mixture is mixed for    about 2 minutes.-   (3) The minoxidil and BHT are added to the beaker and is stirred for    about 10 minutes or until dissolved.-   (4) The water is added slowly and the mixture is mixed for about 2    minutes.-   (5) In a separate second beaker equipped with a hotplate and    magnetic stirrer, steareth-10, steareth-2, cetyl lactate and    tocopheral acetate are premixed to form an oil phase.-   (6) The premix heated to about 60° C. and is stirred with the    magnetic stirring bar until dissolved or melted and oil phase is    uniform.-   (7) The premix is added with stirring to the minoxidil containing    water phase in the first beaker and is mixed for about 5 minutes.-   (8) The sodium pyruvate is added to the first beaker and is mixed    for about 3 minutes.-   (9) The Polyquaternium 37 is added to the first beaker and the    mixture in the first beaker is homogenized at 7,000 rpm using a    Silverson L4RT homogenizer (Silverson, Birmingham, UK) for about 5    minutes.

Example 2 In Vitro Skin Permeation of 5% Minoxidil Compositions throughHuman Cadaver Skin

A skin penetration study evaluated the penetration of minoxidil intodifferent skin layers for the Inventive Treatment Formulation #1 ofExample 1 vs. a commercially available Walgreen's 5% Minoxidil TopicalSolution was used as Comparative Treatment Formulation #2. The pH of theWalgreen's 5% Minoxidil Topical Solution was measured to be 8.1.

A well-known Franz diffusion cell method (as taught in US20020006418 A1,which publication is hereby incorporated by reference) was used. Franzcells had a diameter of 0.5 cm² and a volume of liquid receptor of 5 ml.A magnetic stirrer bar was added in the donor compartment. The liquidreceptor was filled with Phosphate-buffered saline (PBS) solution. Airbubbles in the donor compartment were removed. The system wasthermostated at 37° C. above a magnetic stirrer to ensure thehomogeneity of the liquid receptor during the experiment. A cadaver skinsample from a commercial tissue bank (Ohio Valley Tissue and SkinCenter, Cincinnati, Ohio, dermatomed to approximately 0.4 mm) was cut tofit the glass diffusion cell and mounted skin on the Franz cell. A testsample of 20 microliters was applied on the skin surface. Samples werecollected from the receptor compartment at scheduled time points of 0,1, 3 and 6 hours.

At the end of the study the skin surface was washed with a cotton swabof liquid receptor (PBS). After washing, skin extraction was performedeither on full skin or on separated skin layers of epidermis and dermis.Samples collected from the receptor compartment and from the skinextraction were analyzed for minoxidil levels with a WatersHigh-performance liquid chromatography (HPLC) system with the procedurelisted below. The results are shown in Table 2. The final averageminoxidil levels in different skin layers are reported in micrograms(μg) for 3 different replicates. A minoxidil mass balance study was alsoconducted and the % of recovery of minoxidil was better than 95% forboth the control and the inventive formulation.

HPLC Procedure for Minoxidil Quantification

A HPLC System (Waters Alliance® HPLC system) was used to measureminoxidil with UV absorption response at 286 nm. A Luna 5 μM C18(2)250×4.6-mm HPLC column (Phenomenex) was used to separate the minoxidilanalyte from other impurities in the extract samples for surface rinse,stripped tape, epidermis, dermis, and receptor solution. The mobilephase was an isocratic 80% (70:29:1 water/methanol/acetic acid—pH 3.3):20% methanol.

TABLE 2 Ratio of Inventive Comparative Treatment Treatment InventiveFormulation # 1 Formulation Treatment to Comparative Time # 2Formulation # 1 Treatment (hr) (microgram) (microgram) Formulation # 2Cumulative 3 25.6 24.72132 0.97 Minoxidil in 6 53.1 74.66605 1.40Receptor 24 142. 380.7399 2.68 Dermis 24 15.4 64.68762 4.21 Epidermis 24119.7 203.5053 1.70 Tapes 24 64.7 19.93 0.31 % Recovered 95.5 95.3

Because the target tissue for topical minoxidil delivery is the hairfollicles (or hair “roots”) residing deep in the dermis, only minoxidilthat penetrated into and cross the dermis layer could reach the hairfollicles, and therefore, is of practical significance. The cetyllactate (or a C₈-C₂₄ alcohol ester of a carboxylic acid) containingInventive Treatment Formulation #1 provided significantly enhancedminoxidil delivery deeper into the human skin versus ComparativeTreatment Formulation #2 (i.e., by about 400% into the dermis which iswhere the hair bulb is located), especially in skin tissues, asdemonstrated by the results in Table 2. Moreover, Inventive TreatmentFormulation #1 provided above described higher penetration despiteComparative Treatment Formulation #2 containing signficant amounts oftwo well known skin permeation enhancers, namely ethanol (30%) andpropylene glycol (50%).(See Williams AC1, Barry B W, “Penetrationenhancers” Adv Drug Deliv Rev. 2004 Mar. 27; 56(5):603-18. The InventiveTreatment Formulation #1, by contrast, contains only 20% of ethanol and4% glycol.

Example 3

A mice hair growth study was performed using the hair growthcompositions of the present invention as detailed below.

Procedure:

In vivo hair growth study was conducted in a mouse model similar to thatdescribed in U.S. Pat. No. 6,419,913 B1, which patent is herebyincorporated by reference. Five female mice (C3H mice, Charles RiverBreeding Laboratories, Kingston, N.Y.) were included for each testarticle (i.e., inventive and comparative test formulations of Examples 1and 2).

To determine the acceleration in the onset of the anagen phase in theC3H mice, C3H female mice at 6-7 weeks of age were purchased fromTaconic Farms (Germantown, N.Y.). C3H mice's hair growth cycles havesimilar anagen, catagen and telogen phases. (Miyamoto I.; Hamada K.,Journal of Dermatological Science, Volume 10, Number 1, July 1995, pp.99-99 (1)). The hair growth cycles are shown on Table 3.

TABLE 3 Weeks after Hair Growth Birth Stage Week 0 Morphogenesis Week 2Catagen Week 3 Telogen Week 4 Anagen Week 6 Catagen Week 7 Telogen Week15 Anagen

Each phase is shorter than its corresponding phase in humans andsynchronized. This makes C3H mice a useful model for studying theinduction activity of hair re-growth by active substances. C3H mice havea long telogen window from week 7 to week 15. Therefore, hair regrowthstudies typically start at week 7 and end at week 15, i.e. the durationof a study is about 8 weeks.

Mice were housed in appropriately sized cages in an environmentallycontrolled room with a 12-hour light-12-hour dark photoperiod andsupplied with food and water ad libitum. Animal care was based on the“Guide for the Care and Use of Laboratory Animals”, NIH Publication No.85-23. Once all mice entered their prolonged telogen/resting phase ofthe hair cycle, they were clipped over the dorsal area about 1.5×5 cm(Wahl Clippers 8900 Series, Blade #1086). Five female mice per groupwere clipped while sedated with 2% induction and maintenance isofluraneand 0.5 L Oxygen. The actual number of mice represented in the data mayvary due to inadvertent death of one or more mice during study.

Determination of Accelerated Onset of Anagen Phase

The mice were shaved with a short hair clipper to hairless on their backas determined by visual inspection (2×5 cm² area) at the start of thestudy. Test articles were prepared as described above. The test articleswere applied daily to the shaved areas of the mice daily at 0.2 ml perdose. Both the hair anagen phase and the hair coverage were observed byvisual inspection and recorded 5 days a week for each mouse's haircondition (Telogen phase: resting phase in hair growth cycle—shaved skinshown no dark hair bulbs/roots; Anagen phase: anagen follicles, i.e.follicles in the growth state of the hair growth cycle—shaved skin showsdark hair bulbs/roots) A study log (or, Anagen Phase Log) documentingday-to-day observations of mice entering anagen (grey skin, the firstvisual clue to a new hair growth) were recorded. Treatments continuedfor 8 weeks.

The treatment groups and treatment formulations were selected asfollows:

Group Treatment Formulation A Untreated B Comparative TreatmentFormulation # 2 as described in Example 2 C Inventive TreatmentFormulation # 1 of Example 1

As shown in Table 4 below, the Inventive Treatment Formulation #1resulted in hair follicles turning from resting state (telogen phase) togrowth state (anagen phase) in about four days faster than theComparative Treatment Formulation #2.

TABLE 4 Anagen Phase Onset Log Comparative Treatment Inventive DurationFormulation # 2 Treatment after as described in Formulation # 1treatment Untreated Example 2 of Example 1 Day 1 Telogen Telogen TelogenDay 2 Telogen Telogen Anagen Day 3 Telogen Telogen Anagen Day 6 TelogenAnagen Anagen Week 2 Telogen Anagen Anagen Week 3 Telogen Anagen AnagenWeek 4 Telogen Anagen Anagen Week 5 Telogen Anagen Anagen Week 6 TelogenAnagen Anagen

Table 5 shows anagen phase onsets for Untreated, Comparative TreatmentFormulation #2 and Inventive Treatment Formulation #1 as recorded in theanagen phase log.

TABLE 5 Anagen Phase Onset Anagen Phase Onset Group TreatmentFormulation (Days after Treatment) A Untreated 41 B ComparativeTreatment 6 Formulation # 2 as described in Example 2 C InventiveTreatment 2 Formulation # 1

The data in Table 5 demonstrates that the onset of anagen phase occurred4 days earlier in Group C (Test Formula 2) than in the Group B (TestFormula 1). Group C is 39 days earlier than in Group A of untreated.

The average degree of terminal hair coverage across mice in each Groupwas determined by visual inspection of the images taken weekly. A haircoverage index was used in documenting the mice hair growth stages. Thephrase “degree of terminal hair coverage”, means the observed averageestimated percentage of the treated site which is covered by terminalhair.

The phrase “faster degree of terminal hair coverage” means that a degreeof terminal hair coverage is achieved faster in time. The term “average”means the average across the mice in each group. The term “observed” or“visual observations” means visual inspection.

The groups were then ranked in order of highest degree of terminal haircoverage to lowest degree of terminal hair coverage according to thefollowing hair coverage scoring system.

Hair Coverage Scoring System

Grading Description 0 No hair at all 1 A few patches of hair growth,less than ¼ of the dorsal area 2 Hair growth covering about ¼ of thedorsal area 3 Hair growth covering about ½ of the dorsal area 4 Hairgrowth covering more than ¾ of the dorsal area 5 Hair growth completelycovering treatment area

Table 6 is a ranking of the degree of terminal hair coverage for TestFormulation 1, Test formula 2 and Untreated, based on images taken atdifferent time points. Visual observation of images taken at week 0 (daythat mice were shaved) demonstrated that, at this stage of the study,all the mice of test groups had all terminal hair removed.

TABLE 6 Hair Coverage Score Table for Mice Shaved Hair (n = 5 per cellat the study start) Comparative Treatment Inventive Formulation # 2 asTreatment described in Example 2 Formulation # 1 Untreated IndividualIndividual Aver- Individual Average Score (per Average Score (per ageWeeks Score Score mouse) Score mouse) Score 1 0, 0, 0 0 0 0 1, 1, 1, 1,1 1 2 0, 0, 0 0 1, 1, 1, 1, 1 1 2, 2, 2, 2, 2 2 3 0, 0, 0 0 1, 1, 1, 1,1 1 3, 3, 3, 3, 3 3 4 0, 0, 0 0 1, 1, 1, 1, 1 1 5, 5, 5, 5, 5 5 5 0, 0,0 1, 1, 1, 1, 1 1 5, 5, 5, 5, 5 5 6 0, 0, 0 0 1, 2, 3* 2 5, 5, 5, 5, 5 57 1, 1, 1 1 1, 4, 4* 3 5, 5, 5, 5, 5 5 *Two test mice were sacrificedafter Week 5 evaluation for tissue histologyThe ranking in Table 6 demonstrates that mice skin treated withInventive Treatment Formulation #1 containing the C₈-C₂₄ alcohol esterof a carboxylic acid (i.e., cetyl lactate), demonstrated a much fasterdegree of terminal hair coverage than the Comparative TreatmentFormulation #2.

Example 4

Compositions (e.g., oil in water emulation) or gels incorporating thehair growth composition of the present invention were prepared usingconventional mixing technology and are illustrated as ComparativeFormulation A (withoutthe C₈-C₂₄ alcohol ester of a carboxylic acid) andInventive Treatment Formulation B (with the C₈-C₂₄ alcohol ester of acarboxylic acid) in Table 7.

TABLE 7 Comparative Inventive Treatment Formulation A Formulation BChemical Name % (w/w) % (w/w) Ethyl Alcohol 21.00 21.00 Pentylene Glycol4.00 4.00 Glycerin 12.00 12.00 Citric Acid 0.20 0.20 Lactic Acid 3.003.00 Minoxidil 5.07 5.07 Butylated 0.10 0.10 Hydroxytoluene Steareth-101.50 1.50 Cetyl lactate n/a 1.50 Water 50.63 49.13 Polyquaternium-372.50 2.50 pH = 4.50 100.00 100.00Comparative Formulation A and Inventive Treatment Formulation B wereprepared according to the following procedure:

-   (1) The ethyl alcohol is added to a suitably sized first glass    container with an overhead mixer.-   (2) The pentylene glycol, glycerin, citric acid, & lactic acid are    added to the container and the mixture is mixed for about 2 minutes.-   (3) The minoxidil, and BHT are added to the beaker and is stirred    for about 10 minutes or until dissolved.-   (4) The water is added slowly and the mixture is mixed for about 2    minutes.-   (5) In a separate second beaker equipped with a hotplate and    magnetic stirrer, the steareth-10, and cetyl lactate acetate are    premixed.-   (6) The premix heated to about 60° C. and is stirred with the    magnetic stirring bar until completely melted and a uniform oil    phase is formed.-   (7) The premix is added with stirring to the minoxidil containing    water phase in the first container and is mixed for about 5 minutes.-   (9) The Polyquaternium 37 is added to the first container and the    mixture in the first container is homogenized at 7,000 rpm using a    Silverson L4RT homogenizer (Silverson, Birmingham, UK) for about 5    minutes.

Example 5

In vitro skin permeation of 5% minoxidil compositions through humancadaver skin.

The skin penetration study as described in Example 2 was used toevaluate the penetration of minoxidil into different skin layers for theInventive Treatment Formulation B vs. Comparative Formulation A.

A cadaver skin sample from a commercial tissue bank (Allosource,Centenia, Colo., dermatomed to approximately 0.4 mm) was cut to fit theglass diffusion cell and mounted skin on the Franz cell. A test sampleof 20 microliters was applied on the skin surface. Samples werecollected from the receptor compartment at scheduled time points of 0,2, 4 and 6 hours.

At the end of the study the skin surface was washed with a cotton swabof liquid receptor (PBS). After washing, skin extraction was performedeither on full skin or on separated skin layers of epidermis and dermis.Samples collected from the receptor compartment and from the skinextraction were analyzed for minoxidil levels with a WatersHigh-performance liquid chromatography (HPLC) system with the procedurelisted below. The results are shown in Table 8. The final averageminoxidil levels in different skin layers are reported in micrograms(μg) for 3 different replicates. A minoxidil mass balance study was alsoconducted and the % of recovery of minoxidil was better than 95% forboth the control and the inventive formulation.

HPLC Procedure for Minoxidil Quantification

A HPLC System (Waters Alliance® HPLC system) was used to measureminoxidil with UV absorption response at 286 nm. A Luna 5 μM C18(2)250×4.6-mm HPLC column (Phenomenex) was used to separate the minoxidilanalyte from other impurities in the extract samples for surface rinse,stripped tape, skin (epidermis/dermis), and receptor solution. Themobile phase was an isocratic 80% (70:29:1 water/methanol/acetic acid—pH3.3): 20% methanol.

TABLE 8 Ratio of Inven- tive Treatment Comparative Inventive FormulationB Treatment Treatment to Comparative Time Formulation A Formulation BTreatment (hr) (microgram) (microgram) Formulation A Cumulative 2 58.656.4 0.96 Minoxidil 4 128.8 117.1 0.91 in Receptor 6 185.1 173.5 0.94Skin (Dermal + 6 67.4 138.5 2.06 Epi-dermis) Tapes 6 24.4 56.2 2.31 %Recovered 95.5 95.3

Because the target tissue for topical minoxidil delivery is the hairfollicles (or hair “roots”) residing deep in the dermis, only minoxidilthat penetrated into and cross the skin layer could reach the hairfollicles, and therefore, is of practical significance. The cetyllactate (or C₈-C₂₄ alcohol ester of a carboxylic acid) containingInventive Treatment Formulation B provided significantly enhancedminoxidil delivery deeper into the human skin versus ComparativeFormulation A (i.e., by about 206% into the skin tissues) asdemonstrated by the results in Table 8.

Example 6

Compositions for Comparative Formulation X (without the C₈-C₂₄ alcoholester of a carboxylic acid) and Inventive Formulation Y (with the C₈-C₂₄alcohol ester of a carboxylic acid)

Compositionsincorporating the composition of the present invention canbe prepared using conventional mixing technology and are illustrated asComparative Example X and Inventive Example Y in Table 9.

TABLE 9 Comparative Inventive Formulation X Formulation Y CompositionComposition Chemical Name % (w/w) % (w/w) Ethyl Alcohol 21.00 21.00Pentylene Glycol 4.00 4.00 Glycerin 12.00 12.00 Citric Acid 0.20 0.20Lactic Acid 3.00 3.00 Minoxidil 5.00 5.00 Butylated 0.10 0.10Hydroxytoluene Water 52.70 49.70 Polyquaternium-37 2.00 2.00 CetylLactate N/A 3.00 Total 100.00 100.00Comparative Formulation X and Inventive Formulation Y were preparedaccording to the following procedure:

-   (1) The ethyl alcohol is added to a suitably sized glass container    with an overhead mixer.-   (2) The pentylene glycol, glycerin, citric acid, & lactic acid are    added to the container in the step (1) and the mixture is mixed for    about 2 minutes.-   (3) The minoxidil, and BHT are added to the container and is stirred    for about 10 minutes or until completely dissolved. For Comparative    Formula, skip the process (5) and (6).-   (4) Water is added to the above mixing container. Following with    Polyquaternium-37 added slowly to the mixing container and mixed    until completely dissolved.-   (5) In a separate second glass container equipped with a hotplate    and magnetic stirrer, the premix of cetyl lactate is weighed in and    heated to about 45° C. and is stirred with a magnetic stirring bar    until completely melted.-   (6) The premix is added with stirring to the minoxidil containing    aqueous phase in the first container and is mixed for about 5    minutes.

Example 7

In vitro skin permeation of 5% minoxidil compositions through humancadaver skin.

A skin penetration study evaluated the penetration of minoxidil intodifferent skin layers for the Comparative Formulation X and InventiveFormulation Y.

The skin penetration study as described in Example 2 was used toevaluate the penetration of minoxidil into different skin layers for theComparative Formulation X and Inventive Formulation Y.

A cadaver skin sample from a commercial tissue bank (Allosource,Centenia, Colo., dermatomed to approximately 0.4 mm) was cut to fit theglass diffusion cell and mounted skin on the Franz cell. A test sampleof 20 microliters was applied on the skin surface. Samples werecollected from the receptor compartment at scheduled time points of 0, 6and 24 hours.

At the end of the study the skin surface was washed with a cotton swabof liquid receptor (PBS). After washing, skin extraction was performedeither on full skin or on separated skin layers of epidermis and dermis.Samples collected from the receptor compartment and from the skinextraction were analyzed for minoxidil levels with a Watershigh-performance liquid chromatography (HPLC) system with the procedurelisted below. The results are shown in Table 10. The final averageminoxidil levels in different skin layers are reported in micrograms(μg) for 3 different replicates. A minoxidil mass balance study was alsoconducted and the % of recovery of minoxidil was better than 92.5% forboth the comparative and the inventive formulation.

HPLC Procedure for Minoxidil Quantification

A HPLC System (Waters Alliance® HPLC system) was used to measureminoxidil with UV absorption response at 286 nm. A Luna 5 μM C18(2)250×4.6-mm HPLC column (Phenomenex) was used to separate the minoxidilanalyte from other impurities in the extract samples for surface rinse,stripped tape, epidermis, dermis, and receptor solution. The mobilephase was an isocratic 80% (70:29:1 water/methanol/acetic acid—pH 3.3):20% methanol.

TABLE 10 Ratio of Inventive Comparative Inventive Formulation Y TimeFormulation X Formulation Y to Comparative (hr) (microgram) (microgram)Formulation X Cumulative 0.00 0 0 n/a Minoxidil 6.00 1000 1149 1.1 inReceptor 24.00 2423 2851 1.2 Dermal 24.00 16 77 4.7 Epidermis + 24.00 49236 4.8 Tape % Recovered 92.5 97.5

Because the target tissue for topical minoxidil delivery is the hairfollicles (or hair “roots”) residing deep in the dermis, only thatportion of minoxidil penetrating into and crossing the skin layer couldreach the hair follicles is, therefore, of practical significance. Thecetyl lactate (or C₈-C₂₄ alcohol ester of a carboxylic acid) containingInventive Formulation Y provided significantly enhanced minoxidildelivery deep into the human skin versus Comparative Formulation X (i.e.by about 470% into the dermis), as demonstrated by the results in Table10.

Example 8

A composition incorporating the composition of the present invention canbe prepared using conventional mixing technology and is illustrated inTable 11.

TABLE 11 Theoretical Chemical Name % (w/w) Ethyl Alcohol 53.50 Glycerin3.00 Citric Acid 0.20 Lactic Acid 1.20 Minoxidil 5.00 Butylated 0.10Hydroxytoluene Water 31.50 Hydroxyethylcellulose 1.00 Cetyl Lactate 3.0pH = 5.69 100.00

Example 9

Comparative Treatment formulation A″ and Inventive Treatment formulationB″ (Table 15) are prepared as described below using conventional mixingtechnology.

TABLE 12 Comparative Treatment Inventive Treatment Formulation A″Formulation B″ Ingredient % (wt/wt) % (wt/wt) Ethanol 21.00 21.00Pentylene glycol¹ 4.00 4.00 Glycerin 12.00 12.00 Citric acid 0.20 0.20Lactic acid 3.00 3.00 Minoxidil 5.00 5.00 Butylated 0.10 0.10hydroxytoluene (BHT) Water 43.71 40.71 Cetyl Lactate n/a 3.00 SodiumPyruvate 1.0 1.00 Tocopheryl 0.50 0.50 Acetate Steareth-10 1.50 1.50Steareth -2 2.00 2.00 Cotton seed oil 1.33 1.33 Cocoa butter oil 1.331.33 Olive oil 1.33 1.33 Polyquaternium 37 2.00 2.00 Total 100.00 100.00Apparent pH 4.6 4.6 ¹Hydrolite 5 supplied by (Symrise, Teterboro, NJ)²Cosmedia Ultra 300 supplied by (BASF, Florham Park, N.J)Comparative Treatment Formulation A″ and Inventive Treatment FormulationB″ are prepared according to the following procedure:

-   (1) The ethanol is added to a suitably sized first beaker with an    overhead mixer.-   (2) The pentylene glycol, glycerin, citric acid, & lactic acid,    minoxidil, and BHT are added to the beaker and the mixture is mixed    for about 10 minutes or until dissolved.-   (3) The water is added slowly and the mixture is mixed for about 2    minutes.-   (4) In a separate second beaker equipped with a hotplate and    magnetic stirrer, the steareth-10, steareth-2, tocopheral acetate,    vegetable oils and or cetyl lactate are premixed to form an oil    phase with a heating to about 60° C. and is stirred with the    magnetic stirring bar until dissolved or melted and oil phase is    uniform.-   (5) The premix is added with stirring to the minoxidil containing    water phase in the first beaker and is mixed for about 5 minutes.-   (6) The sodium pyruvate is added to the first beaker and is mixed    for about 3 minutes.-   (7) The Polyquaternium 37 is added to the first beaker and the    mixture in the first beaker is homogenized at 7,000 rpm using a    Silverson L4RT homogenizer (Silverson, Birmingham, UK) for about 5    minutes.

Example 10

In vitro skin permeation of 5% minoxidil compositions through humancadaver skin.

The skin penetration study as described in Example 5 was used toevaluate the penetration of minoxidil into different skin layers for theInventive Treatment Formulation B″ vs. Comparative Formulation A″.

A cadaver skin sample from a commercial tissue bank (Allosource,Centenia, Colo., dermatomed to approximately 0.4 mm) was cut to fit theglass diffusion cell and mounted skin on the Franz cell. A test sampleof 20 microliters was applied on the skin surface. Samples werecollected from the receptor compartment at scheduled time points of 6and 24 hours.

At the end of the study the skin surface was washed with a cotton swabof liquid receptor (PBS). After washing, skin extraction was performedeither on full skin or on separated skin layers of epidermis and dermis.Samples collected from the receptor compartment and from the skinextraction were analyzed for minoxidil levels with a WatersHigh-performance liquid chromatography (HPLC) system with the procedurelisted below. The results are shown in Table 13. The final averageminoxidil levels in different skin layers are reported in micrograms(μg) for 3 different replicates. A minoxidil mass balance study was alsoconducted and the % of recovery of minoxidil was better than 95% forboth the control and the inventive formulation.

HPLC Procedure for Minoxidil Quantification

A HPLC System (Waters Alliance® HPLC system) was used to measureminoxidil with UV absorption response at 286 nm. A Luna 5 μM C18(2)250×4.6-mm HPLC column (Phenomenex) was used to separate the minoxidilanalyte from other impurities in the extract samples for surface rinse,stripped tape/epidermis, dermis, and receptor solution. The mobile phasewas an isocratic 80% (70:29:1 water/methanol/acetic acid—pH 3.3): 20%methanol.

TABLE 13 Ratio of Inventive Treatment Comparative Inventive FormulationB″ Treatment Treatment to Comparative Time Formulation A″ Formulation B″Treatment Location (hr) (microgram) (microgram) Formulation A″Cumulative 6 12 53.2 4.4 Minoxidil 24 23 95 4.1 Receptor Dermis 24 50.175 1.5 Epi + Tape 24 200 235 1.2

Because the target tissue for topical minoxidil delivery is the hairfollicles (or hair “roots”) residing deep in the dermis, only minoxidilthat penetrated into and cross the skin layer could reach the hairfollicles, and therefore, is of practical significance. The cetyllactate (or C₈-C₂₄ alcohol ester of a carboxylic acid) containingInventive Treatment Formulation B″ provided significantly enhancedminoxidil delivery deep into the human skin versus Comparative TreatmentFormulation A″ (i.e. by about 150% into the dermis, as demonstrated bythe results in Table 13.

Example 11

A composition incorporating the composition of the present invention canbe prepared using conventional mixing technology and is illustrated inTable 14.

TABLE 14 Formulation Ingredient % (wt/wt) Ethanol 20.00 Pentyleneglycol¹ 4.00 Glycerin 12.00 Lactic acid 3.20 Minoxidil 5.07 Butylated0.10 hydroxytoluene (BHT) Water 49.36 Cocoa Butter NF 1.33 Olive Oil NF1.33 Cottonseed Oil NF 1.33 Cetyl Lactate⁴ 2.00 Sodium Pyruvate 1.0Tocopheryl Acetate 0.5 Steareth-2³ 1.00 Polyquaternium 37² 2.5 Total100.00 ¹Hydrolite 5 supplied by Symrise, Teterboro, NJ ²Cosmedia Ultra300 supplied by BASF, Florham Park, N.J. ³supplied by Croda, Edison, NJ⁴supplied by Ashland Inc., Covington, KYThe above formulation is prepared according to the following procedure:

-   (1) The ethanol is added to a suitably sized first beaker with an    overhead mixer.-   (2) The pentylene glycol, glycerin, and lactic acid are added to the    beaker and the mixture is mixed for about 2 minutes.-   (3) The minoxidil and BHT are added to the beaker and is stirred for    about 10 minutes or until dissolved.-   (4) The water is added slowly and the mixture is mixed for about 2    minutes.-   (5) In a separate second beaker equipped with a hotplate and    magnetic stirrer, the steareth-2, cetyl lactate and tocopheral    acetate are premixed to form an oil phase.-   (6) The premix heated to about 60° C. and is stirred with the    magnetic stirring bar until dissolved or melted and oil phase is    uniform.-   (7) The premix is added with stirring to the minoxidil containing    water phase in the first beaker and is mixed for about 5 minutes.-   (8) The sodium pyruvate is added to the first beaker and is mixed    for about 3 minutes.-   (9) The Polyquaternium 37 is added to the first beaker and the    mixture in the first beaker is homogenized at 7,000 rpm using a    Silverson L4RT homogenizer (Silverson, Birmingham, UK) for about 5    minutes.

Example 12

Comparative Treatment formulation P and Inventive Treatment formulationQ (Table 15) are prepared as described below using conventional mixingtechnology.

TABLE 15 Comparative Treatment Inventive Treatment Formulation PFormulation Q Ingredient % (wt/wt) % (wt/wt) Ethanol 20.00 20.00Pentylene glycol¹ 4.00 4.00 Glycerin 12.00 12.00 Lactic acid 3.20 3.20Minoxidil 5.07 5.07 Butylated 0.10 0.10 hydroxytoluene (BHT) Water 48.6345.14 Cetyl Lactate⁴ n/a 3.00 Sodium Pyruvate 1.0- 1.00 TocopherylAcetate 0.5- 0.50 Steareth-10³ 3.0 1.50 Steareth -2³ n/a 2.00Polyquaternium 37² 2.5 2.50 Total 100.00 100.00 Apparent pH 4.6 4.6¹Hydrolite 5 supplied by Symrise, Teterboro, NJ ²Cosmedia Ultra 300supplied by BASF, Florham Park, N.J. ³supplied by Croda, Edison, NJ⁴supplied by Ashland Inc., Covington, KYThe formulations P and Q are prepared according to the followingprocedure:

-   (1) The ethanol is added to a suitably sized first beaker with an    overhead mixer.-   (2) The pentylene glycol, glycerin, citric acid (if applicable) and    lactic acid are added to the beaker and the mixture is mixed for    about 2 minutes.-   (3) The minoxidil and BHT are added to the beaker and is stirred for    about 10 minutes or until dissolved.-   (4) The water is added slowly and the mixture is mixed for about 2    minutes.-   (5) In a separate second beaker equipped with a hotplate and    magnetic stirrer, steareth-10, steareth-2 (if applicable), cetyl    lactate (if applicable) and tocopheral acetate are premixed to form    an oil phase.-   (6) The premix heated to about 60° C. and is stirred with the    magnetic stirring bar until dissolved or melted and oil phase is    uniform.-   (7) The premix is added with stirring to the minoxidil containing    water phase in the first beaker and is mixed for about 5 minutes.-   (8) The sodium pyruvate is added to the first beaker and is mixed    for about 3 minutes.-   (9) The Polyquaternium 37 is added to the first beaker and the    mixture in the first beaker is homogenized at 7,000 rpm using a    Silverson L4RT homogenizer (Silverson, Birmingham, UK) for about 5    minutes.

Example 13

In vitro skin permeation of 5% minoxidil compositions through humancadaver skin.

The skin penetration study as described in Example 10 was used toevaluate the penetration of minoxidil into different skin layers for theInventive Treatment Formulation Q of Example 12 vs. a commerciallyavailable Walgreen's 5% Minoxidil Topical Solution which was used asComparative Treatment Formulation R. The apparent pH of the Walgreen's5% Minoxidil Topical Solution was measured to be 8.1. A separate study,as described in Example 10, compared the the penetration of minoxidilinto different skin layers for the Comparative Treatment Formulation Pof Example 12 vs. the commercially available Walgreen's 5% MinoxidilTopical Solution (Comparative Treatment Formulation R).

A cadaver skin sample from a commercial tissue bank (Allosourec,Centennial, Colo., dermatomed to approximately 0.4 mm) was cut to fitthe glass diffusion cell and mounted skin on the Franz cell. A testsample of 20 microliters was applied on the skin surface. Samples werecollected from the receptor compartment at scheduled time points of 0,3, 6 and 24 hours.

At the end of the study the skin surface was washed with a cotton swabof liquid receptor (PBS). After washing, skin extraction was performedeither on full skin or on separated skin layers of epidermis and dermis.Samples collected from the receptor compartment and from the skinextraction were analyzed for minoxidil levels with a WatersHigh-performance liquid chromatography (HPLC) system with the procedurelisted below.

As noted above, the test was performed, comparing Inventive TreatmentFormulation Q versus the Comparative Treatment Formulation R and, thetest was performed again, using a different cadaver from the same skincommercial tissue bank - (Allosourec, Centennial, Colo., dermatomed toapproximately 0.4 mm)—to compare Comparative Treatment Formulation Pversus the Comparative Treatment Formulation R. A comparison ofInventive Treatment Formulation Q versus the Comparative TreatmentFormulation P is extrapolated from the results of the described tests.

The results of the tests and the extrapolation comparison are shown inTables 16 and 17. The final average minoxidil levels in different skinlayers are reported in micrograms (μg) for 3 different replicates. Aminoxidil mass balance study was also conducted and the % of recovery ofminoxidil was better than 95% for both the controls and the inventiveformulation.

HPLC Procedure for Minoxidil Quantification

A HPLC System (Waters Alliance® HPLC system) was used to measureminoxidil with UV absorption response at 286 nm. A Luna 5 μM C18(2)250×4.6-mm HPLC column (Phenomenex) was used to separate the minoxidilanalyte from other impurities in the extract samples for surface rinse,stripped tape, epidermis, dermis, and receptor solution. The mobilephase was an isocratic 80% (70:29:1 water/methanol/acetic acid—pH 3.3):20% methanol.

TABLE 16 Comparative Comparative Inventive Treatment Treatment TreatmentTime Formulation P Formulation R Formulation Q (hr) (microgram)(microgram) (microgram) Cumulative 6 13.7 53.2 0.9 Minoxidil 24 115.0142.2 6.5 in Receptor Dermis 24 24.2 15.4 73.2 Epidermis 24 118.1 119.7163.5 Tape 24 31.5 64.7 67.3

TABLE 17 Minoxidil Skin Penetration Results from tests separatelycomparing_Inventive Treatment Formulation Q vs. Comparative TreatmentFormulation R and Comparative Treatment Formulation P vs. ComparativeTreatment Formulation R Ratio of Ratio of Ratio of Comparative InventiveInventive Treatment Treatment Treatment Formulation P Formulation QFormulation Q to Comparative to Comparative to Comparative TimeTreatment Treatment Treatment (hr) Formulation R Formulation RFormulation P Cumulative 6 0.3 0.02 0.1 Minoxidil 24 0.8 0.05 0.1 inReceptor Dermis 24 1.6 4.8 3.0 Epidermis 24 0.9 1.4 1.5 Tape 24 0.5 1.02.1

Because the target tissue for topical minoxidil delivery is the hairfollicles (or hair “roots”) residing deep in the dermis, only minoxidilthat penetrated into and cross the dermis layer could reach the hairfollicles, and therefore, is of practical significance. The ComparativeTreatment Formulation P and Inventive Treatment Formulations Q providedenhanced minoxidil delivery deep into the human skin versus theComparative Treatment Formulation R (i.e., by about 480% [for InventiveTreatment Formulations Q] and 160% [for Comparative TreatmentFormulation P] into the dermis which is where the hair bulb is located),especially in skin tissues, as demonstrated by the results in Table 17.Additionally, Ratio of test results (micrograms) of Inventive TreatmentFormulation Q to Comparative Treatment Formulation P (micrograms)demonstrates, by extrapolation, a higher penetration of minoxdil intodermis and epidermis using the C₈-C₂₄ alcohol ester of a carboxylic acid(i.e. cetyl lactate).

Example 14

A mice hair growth study was performed using the hair growthcompositions of the present invention as detailed below.

Procedure:

In vivo hair growth study was conducted in a mouse model similar to thatdescribed in Example 3. Five female mice (C3H mice, Charles RiverBreeding Laboratories, Kingston, N.Y.) were included for each testarticle.

To determine the acceleration in the onset of the anagen phase in theC3H mice, C3H female mice at 6-7 weeks of age were purchased fromTaconic Farms (Germantown, N.Y.). C3H mice's hair growth cycles havesimilar anagen, catagen and telogen phases. (Miyamoto I.; Hamada K.,Journal of Dermatological Science, Volume 10, Number 1, July 1995, pp.99-99 (1)). The hair growth cycles are shown on Table 18.

TABLE 18 Weeks after Birth Hair Growth Stage Week 0 Morphogenesis Week 2Catagen Week 3 Telogen Week 4 Anagen Week 6 Catagen Week 7 Telogen Week15 Anagen

Each phase is shorter than its corresponding phase in humans andsynchronized. This makes C3H mice a useful model for studying theinduction activity of hair re-growth by active substances. C3H mice havea long telogen window from week 7 to week 15. Therefore, hair regrowthstudies typically start at week 7 and end at week 15, i.e. the durationof a study is about 8 weeks.

Mice were housed in appropriately sized cages in an environmentallycontrolled room with a 12-hour light-12-hour dark photoperiod andsupplied with food and water ad libitum. Animal care was based on the“Guide for the Care and Use of Laboratory Animals”, NIH Publication No.85-23. Once all mice entered their prolonged telogen/resting phase ofthe hair cycle, they were clipped over the dorsal area about 1.5×5 cm(Wahl Clippers 8900 Series, Blade #1086). Five female mice per groupwere clipped while sedated with 2% induction and maintenance isofluraneand 0.5 L Oxygen. The actual number of mice represented in the data mayvary due to inadvertent death of one or more mice during study.

Determination of Accelerated Onset of Anagen Phase

The mice were shaved with a short hair clipper to hairless on their backas determined by visual inspection (2×5cm² area) at the start of thestudy. Test articles were prepared as in the procedures described above.The test articles were applied daily to the shaved areas of the micedaily at 0.2 ml per dose. Both the hair anagen phase and the haircoverage were observed by visual inspection and recorded 5 days a weekfor each mouse's hair condition (Telogen phase: resting phase in hairgrowth cycle—shaved skin shown no dark hair bulbs/roots; Anagen phase:anagen follicles, i.e. follicles in the growth state of the hair growthcycle—shaved skin shows dark hair bulbs/roots) A study log (or, AnagenPhase Log) documenting day-to-day observations of mice entering anagen(grey skin, the first visual clue to a new hair growth) were recorded.Treatments continued for 8 weeks.

The treatment groups and treatment formulations were selected asfollows:

Group Treatment Formulation A Untreated B Comparative TreatmentFormulation R C Comparative Treatment Formulation P D InventiveTreatment Formulation Q

As shown in Table 19 below, the Inventive Composition Formula Q resultedin hair follicles turning from resting state (telogen phase) to growthstate (anagen phase) in about three days faster than the ComparativeTreatment Formulation R. The Inventive Composition Formula Q resulted inhair follicles turning from resting state (telogen phase) to growthstate (anagen phase) in about four days faster than the ComparativeTreatment Formulation R.

TABLE 19 Anagen Phase Onset Log Duration Comparative ComparativeInventive after Treatment Treatment Composition treatment UntreatedFormulation R Formulation P Formula Q Day 1 Telogen Telogen TelogenTelogen Day 2 Telogen Telogen Telogen Anagen Day 3 Telogen TelogenAnagen Anagen Day 6 Telogen Anagen Anagen Anagen Week 2 Telogen AnagenAnagen Anagen Week 3 Telogen Anagen Anagen Anagen Week 4 Telogen AnagenAnagen Anagen Week 5 Telogen Anagen Anagen Anagen Week 6 Telogen AnagenAnagen Anagen

Table 20 shows anagen phase onset times for Untreated, ComparativeTreatment Formulation R, Comparative Treatment Formulation P andInventive Treatment Formulation Q as recorded in the anagen phase log.

TABLE 20 The Anagen Phase Onset Anagen Phase Onset Group TreatmentFormulation (Days after Treatment) A Untreated 41 B ComparativeTreatment 6 Formulation R C Comparative Treatment 3 Formulation P DInventive Treatment 2 Formulation Q

The data in Table 20 demonstrates that the onset of anagen phaseoccurred 3 days earlier in Group C (Comparative Treatment Formulation P)and four days earlier in Group D (Inventive Treatment Formulation Q)than in the Group B (Comparative Treatment Formulation R). Group C is 38days while Group D is 39 days earlier than in Group A of untreated.

The average degree of terminal hair coverage across mice in each Groupwas determined by visual inspection of the images taken weekly. A haircoverage index was used in documenting the mice hair growth stages. Thephrase “degree of terminal hair coverage”, means the observed averageestimated percentage of the treated site which is covered by terminalhair.

The phrase “faster degree of terminal hair coverage” means that a degreeof terminal hair coverage is achieved faster in time. The term “average”means the average across the mice in each group. The term “observed” or“visual observations” means visual inspection.

The groups were then ranked in order of highest degree of terminal haircoverage to lowest degree of terminal hair coverage according to thefollowing hair coverage scoring system.

Hair Coverage Scoring System

Grading Description 0 No hair at all 1 A few patches of hair growth,less than ¼ of the dorsal area 2 Hair growth covering about ¼ of thedorsal area 3 Hair growth covering about ½ of the dorsal area 4 Hairgrowth covering more than ¾ of the dorsal area 5 Hair growth completelycovering treatment area

Table 21 is a ranking of the degree of terminal hair coverage forComparative Treatment Formulation P, Comparative Treatment FormulationR, Inventive Treatment Formulation Q and Untreated, based on imagestaken at different time points. Visual observation of images taken atweek 0 (day that mice were shaved) demonstrated that, at this stage ofthe study, all the mice of test groups had all terminal hair removed.

TABLE 21 Hair Coverage Score Table for Mice Shaved Hair (n = 5 per cellat the study start Inventive Comparative Comparative CompositionTreatment Treatment Treatment Formula Formulation R Formulation P Q WeekUntreated Individual Individual Individual Individual Ave. Score (perAve. Score (per Ave. Score (per Ave. Week Score Score mouse) Scoremouse) Score mouse) Score 1 0, 0, 0 0 0, 0, 0, 0, 0 0 2, 1, 2, 3, 3 2 1,1, 1, 1, 1 1 2 0, 0, 0 0 1, 1, 1, 1, 1 1 0, 1, 1, 1, 2 1 2, 2, 2, 2, 2 23 0, 0, 0 0 1, 1, 1, 1, 1 1 3, 3, 3, 3 3 3, 3, 3, 3, 3 3 4 0, 0, 0 0 1,1, 1, 1, 1 1 4, 4, 5, 5* 4.5 5, 5, 5, 5, 5 5 5 0, 0, 0 1, 1, 1, 1, 1 1 —— 5, 5, 5, 5, 5 5 6 0, 0, 0 0 1, 2, 3* 2 5, 5, 5, 5* 5 5, 5, 5, 5, 5 5 71, 1, 1 1 1, 4, 4* 3 5, 5, 5, 5** 5 5, 5, 5, 5, 5 5 *One test mice wassacrificed after Week 4 evaluation for tissue histology

The ranking in Table 6 demonstrates that mice skin treated withInventive Treatment Formulation Q, containing the non-ionic lipid(steareth-10) and C₈-C₂₄ alcohol ester of a carboxylic acid (i.e., cetyllactate), demonstrated a much faster degree of terminal hair coveragethan the Comparative Treatment Formulation R containing the non-ioniclipid (steareth-10) and no C₈-C₂₄ alcohol ester of a carboxylic acid(i.e., cetyl lactate). However, it was surprising that the hair startedto fall off from newly growing areas with the treatment of theComparative Treatment Formulation R. The Inventive Treatment FormulationQ containing the C₈-C₂₄ alcohol ester of a carboxylic acid (i.e., cetyllactate) in addition to the the non-ionic lipid (steareth-10) did notshow this hair falling off effect and it grew the mice hair the fastest.

Example 15

Compositions incorporating the hair growth composition of the presentinvention were prepared using conventional mixing technology and Exampleformula I and II are illustrated in Table 22.

TABLE 22 Comparative Formulation I and Inventive Treatment FormulationII Inventive Comparative Treatment Formulation I Formulation II ChemicalName % (w/w) % (w/w) Ethyl Alcohol 21.00 21.00 Pentylene Glycol 4.004.00 Glycerin 12.00 12.00 Citric Acid 0.20 0.20 Lactic Acid 3.00 3.00Minoxidil 5.07 5.07 Butylated 0.10 0.10 Hydroxytoluene Steareth-10 1.501.50 Cetyl lactate n/a 1.50 Water 50.63 49.13 Polyquaternium-37 2.502.50 pH = 4.50 100.00 100.00Comparative Formulation I and Inventive Treatment Formulation II wereprepared according to the following procedure:

-   (1) The ethyl alcohol is added to a suitably sized first glass    container with an overhead mixer.-   (2) The pentylene glycol, glycerin, citric acid, & lactic acid are    added to the container and the mixture is mixed for about 2 minutes.-   (3) The minoxidil, and BHT are added to the beaker and is stirred    for about 10 minutes or until dissolved.-   (4) The water is added slowly and the mixture is mixed for about 2    minutes.-   (5) In a separate second beaker equipped with a hotplate and    magnetic stirrer, the steareth-10, and cetyl lactate acetate are    premixed.-   (6) The premix heated to about 60° C. and is stirred with the    magnetic stirring bar until completely melted and a uniform oil    phase is formed.-   (7) The premix is added with stirring to the minoxidil containing    water phase in the first container and is mixed for about 5 minutes.-   (9) The Polyquaternium 37 is added to the first container and the    mixture in the first container is homogenized at 7,000 rpm using a    Silverson L4RT homogenizer (Silverson, Birmingham, UK) for about 5    minutes.

Example 16

In vitro skin permeation of 5% minoxidil compositions through humancadaver skin.

The skin penetration study as described in Example 5 was used toevaluate the penetration of minoxidil into different skin layers for theInventive Treatment Formulation II vs. Comparative Formulation I.

A cadaver skin sample from a commercial tissue bank (Allosource,Centenia, Colo., dermatomed to approximately 0.4 mm) was cut to fit theglass diffusion cell and mounted skin on the Franz cell. A test sampleof 20 microliters was applied on the skin surface. Samples werecollected from the receptor compartment at scheduled time points of 0,2, 4 and 6 hours.

At the end of the study the skin surface was washed with a cotton swabof liquid receptor (PBS). After washing, skin extraction was performedeither on full skin or on separated skin layers of epidermis and dermis.Samples collected from the receptor compartment and from the skinextraction were analyzed for minoxidil levels with a WatersHigh-performance liquid chromatography (HPLC) system with the procedurelisted below. The results are shown in Table 23. The final averageminoxidil levels in different skin layers are reported in micrograms(μg) for 3 different replicates. A minoxidil mass balance study was alsoconducted and the % of recovery of minoxidil was better than 95% forboth the control and the inventive formulation.

HPLC Procedure for Minoxidil Quantification

A HPLC System (Waters Alliance® HPLC system) was used to measureminoxidil with UV absorption response at 286 nm. A Luna 5 μM C18(2)250×4.6-mm HPLC column (Phenomenex) was used to separate the minoxidilanalyte from other impurities in the extract samples for surface rinse,stripped tape, skin (epidermis/dermis), and receptor solution. Themobile phase was an isocratic 80% (70:29:1 water/methanol/acetic acid—pH3.3): 20% methanol.

TABLE 23 Ratio of Inventive Inventive Treatment Comparative TreatmentFormulation II Time Formulation I Formulation II to Comparative (hr)(microgram) (microgram) Formulation I Cumulative 2 58.6 56.4 0.96Minoxidil in 4 128.8 117.1 0.91 Receptor 6 185.1 173.5 0.94 Skin 6 67.4138.5 2.06 Tapes 6 24.4 56.2 2.31 % Recovered 95.5 95.3

Because the target tissue for topical minoxidil delivery is the hairfollicles (or hair “roots”) residing deep in the dermis, only minoxidilthat penetrated into and cross the skin layer could reach the hairfollicles, and therefore, is of practical significance. The cetyllactate (or C₈-C₂₄ alcohol ester of a carboxylic acid) containingInventive Treatment Formulation II provided significantly enhancedminoxidil delivery deeper into the human skin versus ComparativeFormulation I (i.e., by about 206% into the skin tissues) asdemonstrated by the results in Table 23.

Example 17

Additional compositions incorporating the composition of the presentinvention can be prepared using conventional mixing technology (or, asdescribed in Example 1) and are illustrated in Examples j-o of Table 24.

TABLE 24 j K l m n o Chemical Name % (w/w) % (w/w) % (w/w) % (w/w) %(w/w) % (w/w) Ethyl Alcohol 21 21 53.5 30 25 15 Pentylene glycol — — —10 3 — Propylene glycol 10 10 — 1 1 5 Steareth-10 1.5 1.5 — 1 1 —Steareth-2 2.0 2.0 — — — — Glyceryl Stearate — — — 1 0.5 — Glycerin 1010 3 10 12 10 Citric Acid — — 0.2 0.1 0.1 0.1 Lactic Acid 3.0 3.0 1.2 12.4 3.2 Minoxidil 5.0 5.0 5 10 5 3 Butylated 0.1 0.1 0.1 0.1 0.1 0.1Hydroxytoluene Water 43.83 43.83 33 34.3 46.9 59.6Carboxymethylcellulose 0.75 0.50 — — — — Hydroxyethylcellulose — — 1 1 11 Mixture of C₁₂₋₁₅ 3.0 3.0 1.5 1.5 — — Alkyl Lactate¹ Cetyl Lactate — —1.5 — 3 3 Total 100 100 100 100 100 100 Viscosity (cps) 13000 8650 NotNot Not Not measured measured measured measured Physical stability at 4°C. stable stable Not Not Not Not measured measured measured measuredPhysical stability at stable stable Not Not Not Not 40° C. measuredmeasured measured measured ¹Supplied by Ashland (NJ, USA)Examples j and k of Table 24 show that compositions comprisingcarboxymethylcelluose and the mixture of C₁₂₋₁₅ alkyl lactate showphysical stability (i.e., no phase separation) at temperatures as low as4° C. and as high as 40° C. after 1 week of storage at each suchtemperature as described above.

Example 18

Hair growth compositions of the present invention incorporating selectratios of nonionic hydroxypropylmethyl cellulose (HPMC) to highmolecular weight carboxymethyl cellulose (CMC) were prepared usingconventional mixing technology. These compositions showed stabilityafter 1 week of storage (at 4° C. and 40° C.) as described above and aredetailed as Inventive Treatment Formulations QQ, RR and SS in Table 25.

TABLE 25 Inventive Treatment Formulations QQ, RR and SS InventiveInventive Inventive Treatment Treatment Treatment FormulationFormulation Formulation Chemical Name QQ RR SS Ethyl Alcohol 21.00 21.0021.00 Propylene Glycol 10.00 10.00 10.00 Glycerin 10.00 10.00 10.00Citric Acid 0.20 0.20 0.20 Lactic Acid 3.00 3.00 3.00 Minoxidil 5.005.00 5.00 Butylated 0.10 0.10 0.10 Hydroxytoluene Water 44.40 44.1543.20 Carboxymethylcellulsoe 0.25 0.25 0.25 sodium saltHydroxypropylmethyl 0.75 1.00 0.75 cellulose Steareth-2 1.3 1.3 2.00Steareth-10 1.00 1.00 1.50 Myristyl Lactate 3.00 3.00 3.00 Total 100 100100 Physical stability stable stable stable at 4° C. Physical stabilitystable stable stable at 40° C.Inventive Treatment Formulations QQ, RR and SS were each preparedaccording to the following procedure:

-   (1) The ethyl alcohol is added to a suitably sized first glass    container with an overhead mixer.-   (2) The propylene glycol, glycerin, citric acid, & lactic acid are    added to the container and the mixture is mixed for about 2 minutes.-   (3) The minoxidil, and BHT are added to the beaker and is stirred    for about 10 minutes or until dissolved.-   (4) The water is added slowly and the mixture is mixed for about 2    minutes.-   (5) In a separate second beaker equipped with a hotplate and    magnetic stirrer, the steath, 2, steareth-10, and myristyl lactate    acetate are premixed.-   (6) The premix heated to about 60° C. and is stirred with the    magnetic stirring bar until completely melted and a uniform oil    phase is formed.-   (7) The premix is added with stirring to the minoxidil containing    water phase in the first container and is mixed for about 5 minutes.-   (9) The CMC and HPMC are added to the first container and the    mixture in the first container is homogenized at 7,000 rpm using a    Silverson L4RT homogenizer (Silverson, Birmingham, UK) for about 5    minutes.

Example 19

A mice hair growth study was performed using the hair growthcompositions of the present invention Inventive Treatment FormulationsQQ, RR and SS vs. a commercially available Walgreen's 5% MinoxidilTopical Solution was used as Comparative Formulation TT. (The pH of theWalgreen's 5% Minoxidil Topical Solution was measured to be 8.1.)

Procedure:

In vivo hair growth study was conducted in a mouse model similar to thatdescribed in U.S. Pat. No. 6,419,913 B1, which patent is herebyincorporated by reference. Five female mice (C3H mice, Charles RiverBreeding Laboratories, Kingston, N.Y.) were included for each testarticle (i.e., inventive and comparative test formulations of Examples 1and 2).

To determine the acceleration in the onset of the anagen phase in theC3H mice, C3H female mice at 6-7 weeks of age were purchased fromTaconic Farms (Germantown, N.Y.). C3H mice's hair growth cycles havesimilar anagen, catagen and telogen phases. (Miyamoto I.; Hamada K.,Journal of Dermatological Science, Volume 10, Number 1, July 1995, pp.99-99 (1)). The hair growth cycles are shown on Table 26.

TABLE 26 Weeks after Birth Hair Growth Stage Week 0 Morphogenesis Week 2Catagen Week 3 Telogen Week 4 Anagen Week 6 Catagen Week 7 Telogen Week15 Anagen

Each phase is shorter than its corresponding phase in humans andsynchronized. This makes C3H mice a useful model for studying theinduction activity of hair re-growth by active substances. C3H mice havea long telogen window from week 7 to week 15. Therefore, hair regrowthstudies typically start at week 7 and end at week 15, i.e. the durationof a study is about 8 weeks.

Mice were housed in appropriately sized cages in an environmentallycontrolled room with a 12-hour light-12-hour dark photoperiod andsupplied with food and water ad libitum. Animal care was based on the“Guide for the Care and Use of Laboratory Animals”, NIH Publication No.85-23. Once all mice entered their prolonged telogen/resting phase ofthe hair cycle, they were clipped over the dorsal area about 1.5×5 cm(Wahl Clippers 8900 Series, Blade #1086). Five female mice per groupwere clipped while sedated with 2% induction and maintenance isofluraneand 0.5 L Oxygen. The actual number of mice represented in the data mayvary due to inadvertent death of one or more mice during study.

Determination of Accelerated Onset of Anagen Phase

The mice were shaved with a short hair clipper to hairless on their backas determined by visual inspection (2×5 cm² area) at the start of thestudy. Test articles were prepared as described above. The test articleswere applied daily to the shaved areas of the mice daily at 0.2 ml perdose. Both the hair anagen phase and the hair coverage were observed byvisual inspection and recorded 5 days a week for each mouse's haircondition (Telogen phase: resting phase in hair growth cycle—shaved skinshown no dark hair bulbs/roots; Anagen phase: anagen follicles, i.e.follicles in the growth state of the hair growth cycle—shaved skin showsdark hair bulbs/roots) A study log (or, Anagen Phase Log) documentingday-to-day observations of mice entering anagen (grey skin, the firstvisual clue to a new hair growth) were recorded. Treatments continuedfor 8 weeks.

The treatment groups and treatment formulations were selected asfollows:

Group Treatment Formulation A Untreated B Comparative Formulation TT CInventive Treatment Formulation QQ D Inventive Treatment Formulation RRE Inventive Treatment Formulation SS

As shown in Table 27 below, the Inventive Treatment Formulations QQ, RRand SS each resulted in hair follicles turning from resting state(telogen phase) to growth state (anagen phase) in about four days fasterthan the Comparative Treatment Formulation TT.

TABLE 27 Anagen Phase Onset Log Inventive Inventive Treatment TreatmentInventive Compar- Duration Formula- Formula- Treatment ative after Un-tion QQ tion RR Formula- Formula- treatment treated (microgram)(microgram) tion SS tion TT Day 1 Telogen Telogen Telogen TelogenTelogen Day 2 Telogen Anagen Anagen Anagen Telogen Day 3 Telogen AnagenAnagen Anagen Telogen Day 6 Telogen Anagen Anagen Anagen Anagen Week 2Telogen Anagen Anagen Anagen Anagen Week 3 Telogen Anagen Anagen AnagenAnagen Week 4 Telogen Anagen Anagen Anagen Anagen Week 5 Telogen AnagenAnagen Anagen Anagen Week 6 Telogen Anagen Anagen Anagen Anagen

Table 28 shows anagen phase onsets for Untreated, Comparative TreatmentFormulation TT and Inventive Treatment Formulations QQ, RR and SS asrecorded in the anagen phase log.

TABLE 28 Anagen Phase Onset Anagen Phase Onset Group TreatmentFormulation (Days after Treatment) A Untreated 42 B ComparativeFormulation TT 6 C Inventive Treatment 2 Formulation QQ D InventiveTreatment 2 Formulation RR E Inventive Treatment 2 Formulation SS

The data in Table 28 demonstrates that the onset of anagen phaseoccurred 4 days earlier in Group C (Test Formula 2) than in the Group B(Test Formula 1). Group C is 40 days earlier than in Group A ofuntreated.

The average degree of terminal hair coverage across mice in each Groupwas determined by visual inspection of the images taken weekly. A haircoverage index was used in documenting the mice hair growth stages. Thephrase “degree of terminal hair coverage”, means the observed averageestimated percentage of the treated site which is covered by terminalhair.

The phrase “faster degree of terminal hair coverage” means that a degreeof terminal hair coverage is achieved faster in time. The term “average”means the average across the mice in each group. The term “observed” or“visual observations” means visual inspection.

The groups were then ranked in order of highest degree of terminal haircoverage to lowest degree of terminal hair coverage according to thefollowing hair coverage scoring system.

Hair Coverage Scoring System

Grading Description 0 No hair at all 1 A few patches of hair growth,less than ¼ of the dorsal area 2 Hair growth covering about ¼ of thedorsal area 3 Hair growth covering about ½ of the dorsal area 4 Hairgrowth covering more than ¾ of the dorsal area 5 Hair growth completelycovering treatment area

Table 29 is a ranking of the degree of terminal hair coverage for TestFormulation 1, Test formula 2 and Untreated, based on images taken atdifferent time points. Visual observation of images taken at week 0 (daythat mice were shaved) demonstrated that, at this stage of the study,all the mice of test groups had all terminal hair removed.

TABLE 29 Hair Coverage Score Table for Mice Shaved Hair (n = 5 per cellat the study start) Inventive Inventive Inventive Comparative TreatmentTreatment Treatment Untreated Formulation TT Formulation QQ FormulationSS Formulation RR Hair Coverage Hair Coverage Hair Coverage HairCoverage Hair Coverage Score Score Score Score Score Week Per mouse Ave.Per mouse Ave. Per mouse Ave. Per mouse Ave. Per mouse Ave. 1 0, 0, 0,0, 0 0 0, 0, 0, 0, 0 0 1, 1, 1, 0.5, 0.5 0.8 1, 1, 1, 0.5, 0.5 0.8 0.5,0.5, 1, 1, 1 0.8 2 0, 0, 0, 0, 0 0 0, 0, 0, 0, 1 0.2 1, 1, 1.5, 1, 0.51.0 2, 1, 1.5, 1, 0.5 1.2 1, 1, 1, 1, 1.5 1.1 3 0, 0, 0, 0, 0 0 0, 0, 1,1, 2 0.8 2, 3, 4, 4, 4 3.4 5, 3, 4, 3, 3 3.6 3, 3, 3, 4, 5 3.7 4 0, 0,0, 0, 0 0 0, 1, 1, 2, 2 1.2 5, 5, 5, 5, 5 5 5, 5, 5, 5, 5 5 5, 5, 5, 5,5 5 5 0, 0, 0, 0, 0 0 0.5.1, 2, 2, 4 1.9 5, 5, 5, 5, 5 5 5, 5, 5, 5, 5 55, 5, 5, 5, 5 5 6 0, 0, 0, 0, 1 0.2 1, 3, 4, 4, 5 3.4 5, 5, 5, 5, 5 5 5,5, 5, 5, 5 5 5, 5, 5, 5, 5 5 7 0, 0, 0, 0, 1 0.2 2, 4, 4, 5, 5 4 5, 5,5, 5, 5 5 5, 5, 5, 5, 5 5 5, 5, 5, 5, 5 5The ranking in Table 29 demonstrates that mice skin treated withInventive Treatment Formulations QQ, RR, and SS containing myristallactate demonstrated a much faster degree of terminal hair coverage thanthe Comparative Formulation TT.

Example 20

Formulation examples p-v are compositions incorporating the compositionof the present invention. The compositions of examples p-v compriseselect ratios of nonionic hydroxypropylmethyl cellulose (HPMC) to highmolecular weight carboxymethyl cellulose (CMC) and can be prepared usingconventional mixing technology (or, as described in Example 18) and areillustrated in Table 30 and showing stability assessment after 1 week ofstorage (at 4° C. and 40° C.) as described above under definition ofstorage stability.

TABLE 30 Assessment of Temperature Stability after 1 Week of Storage p qr s t u v Chemical Name % (w/w) % (w/w) % (w/w) % (w/w) % (w/w) % (w/w)% (w/w) Ethyl Alcohol 21.00 21.00 21.00 21.00 21.00 21.00 21.00Propylene Glycol 10.00 10.00 10.00 10.00 10.00 10.00 10.00 Glycerin10.00 10.00 10.00 10.00 10.00 10.00 10.00 Citric Acid 0.20 0.20 0.200.20 0.20 0.20 0.20 Lactic Acid 3.00 3.00 3.00 3.00 3.00 3.00 3.00Minoxidil 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Butylated 0.10 0.10 0.100.10 0.10 0.10 0.10 Hydroxytoluene Water 44.40 44.40 44.40 44.40 44.4044.40 43.90 Carboxymethylcellulose 0.25 0.33 0.50 0.67 1.00 0.00 0.75sodium salt (CMC)¹ Hydroxypropylmethyl 0.75 0.67 0.50 0.33 0.00 1.000.75 cellulose (HPMC)² Steareth-2 1.30 1.30 1.30 1.30 1.30 1.30 1.30Steareth-10 1.00 1.00 1.00 1.00 1.00 1.00 1.00 Myristyl Lactate 3.003.00 3.00 3.00 3.00 3.00 3.00 Total 100 100 100 100 100 100 100 Physicalstability at 4° C. stable stable stable unstable unstable stable stablePhysical stability at 40° C. stable stable stable stable stable unstablestable Ratio of 3:1 2:1 1:1 1:2 0:1 1:0 1:1 HPMC vs. CMC Viscosity* 3433cps 5933 cps 7266 cps 12100 cps 23800 cps 1050 cps 17000 cps Totalconcentration of 1.00 1.00 1.00 1.00 1.00 1.00 1.50 *Measured using aBrookfield RV (spindle 4, speed 6 RPM at 1 minute following thetemperature equilibration at 25° C. ± 1° C.) ¹Aqualon CMC 7HF PH,Ashland, Wilmington, DE, USA ²Methocel E 10M, Dow Chemical, Miland, MC,USATable 30 shows that examples p through r and v, having ratios of HPMC toCMC of 3:1, 2:1 and 1:1, respectively, provide compositions which arephysically stable (i.e., no phase separation) at temperatures as low as4° C. and as high as 40° C. after 1 week of storage at each suchtemperature as described above. Table 30 further demonstrates thatratios of HPMC to CMC below 1:1 or greater than 10:1, as in examples s-u(ratios of HPMC to CMC of 1:2, 0:1 and 1:0, respectively), fail toprovide the physical stability at both 4° C. and 40° C. after 1 week ofstorage.

Example 21

The stability of the compositions of formulation examples p-v of Example20 were reassessed after 7 weeks of storage. The formulations ofexamples p-v of Example 20 are reproduced in Table 31, includingstability assessment after 7 weeks of storage (at 4° C. and 40° C.) asdescribed above under definition of storage stability.

TABLE 31 Assessment of Temperature Stability after 7 Weeks of Storage pq r s t u v Chemical Name % (w/w) % (w/w) % (w/w) % (w/w) % (w/w) %(w/w) % (w/w) Ethyl Alcohol 21.00 21.00 21.00 21.00 21.00 21.00 21.00Propylene Glycol 10.00 10.00 10.00 10.00 10.00 10.00 10.00 Glycerin10.00 10.00 10.00 10.00 10.00 10.00 10.00 Citric Acid 0.20 0.20 0.200.20 0.20 0.20 0.20 Lactic Acid 3.00 3.00 3.00 3.00 3.00 3.00 3.00Minoxidil 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Butylated 0.10 0.10 0.100.10 0.10 0.10 0.10 Hydroxytoluene Water 44.40 44.40 44.40 44.40 44.4044.40 43.90 Carboxymethylcellulose 0.25 0.33 0.50 0.67 1.00 0.00 0.75sodium salt (CMC)¹ Hydroxypropylmethyl 0.75 0.67 0.50 0.33 0.00 1.000.75 cellulose (HPMC)² Steareth-2 1.30 1.30 1.30 1.30 1.30 1.30 1.30Steareth-10 1.00 1.00 1.00 1.00 1.00 1.00 1.00 Myristyl Lactate 3.003.00 3.00 3.00 3.00 3.00 3.00 Total 100 100 100 100 100 100 100 Physicalstability at 4° C. stable unstable unstable unstable unstable stableunstable Physical stability at 40° C. stable stable stable stable stableunstable stable Ratio of 3:1 2:1 1:1 1:2 0:1 1:0 1:1 HPMC vs. CMCViscosity* 3433 cps 5933 cps 7266 cps 12100 cps 23800 cps 1050 cps 17000cps Total concentration of 1.00 1.00 1.00 1.00 1.00 1.00 1.50 *Measuredusing a Brookfield RV (spindle4, speed 6 RPM at 1 minute following thetemperature equilibration at 25° C. ± 1° C.) ¹Aqualon CMC 7HF PH,Ashland, Wilmington, DE, USA ²Methocel E 10M, Dow Chemical, Miland, MC,USATable 31 shows that example p, having a ratio of HPMC to CMC of 3:1,provides compositions which are physically stable (i.e., no phaseseparation) at temperatures as low as 4° C. and as high as 40° C. after7 weeks of storage at each such temperature as described above. Table 31further demonstrates that ratios of HPMC to CMC below 3:1 or greaterthan 10:1 (as in examples q-v) fail to provide stability at both 4° C.and 40° C. after 7 weeks. Example 22 Formulation examples i-ix ofExample 22 are compositions incorporating the composition of the presentinvention. These examples i-ix comprise monohydric alcohols and dihydricalcohols at a total of concentration greater than 36% (w/w) of the totalcomposition (due to the higher alkyl lactate concentrations [i.e.,greater 1% by weight of total composititon]) and can be prepared usingconventional mixing technology (or, as described in Example 1). Theseexamples i-ix are detailed in Table 32 and 33.

TABLE 33 vi % vii % viii % ix % Chemical Name (w/w) (w/w) (w/w) (w/w)Ethyl Alcohol 21 26 21 30 Propylene glycol 20.0 20.0 15.0 10.0 Glycerin— — 5.0 10.0 Citric Acid 0.11 0.11 0.2 — Lactic Acid 3.0 3.0 3.0 3.0Minoxidil 5.0 5.0 5.0 5.0 Butylated 0.1 0.1 0.1 0.1 Hydroxytoluene Water46.29 41.04 45.2 37.4 Hypromellose 1.0 1.0 1.0 1.0 Steareth-10 0.5 0.751.5 0.5 Myristyl Lactate 3.0 3.0 3.0 3.0 Total 100 100 100 100 Physicalstability Stable Stable Stable Stable at 4° C. Physical stability HazyHazy Hazy, Stable at 25° C. in 6 months Clear Physical stability StableStable- Physical Stable at 40° C. Hazy Hazy Separation Clear Viscosity(cps) 1020 1340 880 1680 Turbidity (NTU) 66.5 35.2 41.5 1.13 RelativeDielectric 0.112 0.138 0.118 0.178 Constant Index (RI)Table 32 shows that examples i-iv are “clear” and “stable”. Table 32further shows that examples i-iv have turbidities of less than 6 NTU.For Example v, Table 32 shows mixed results—i.e., for a turbiditygreater than 6, we have slight haziness and stability at 4° C. and 25°C., physical separation at 40° C. Table 33 show that examples vi-viiiare not stable and hazy where, in each case, the turbidity is above 10NTU. Example ix was stable and clear with a turbidity lower than 6 NTU.Table 33 further shows that the composition having an RI (as definedabove) of greater than 0.15 (i.e., Example ix [RI=0.178], in contrast toExamples vi-viii [RI equal to 0.112, 0.138, and 0.118, respectively]) isobserved to be a “clear” composition.

What is claimed is:
 1. A composition comprising: a. liquid vesiclescomprising: i. one or more of a hair growth or hair regrowth compoundrepresented by formulas I or II:

and mixtures thereof, wherein R¹ is hydrogen or —N(R³)(R⁴), each R³ andR⁴ individually is selected from the group consisting of hydrogen, loweralkyl, lower alkenyl, lower aralkyl, and lower cycloalkyl, and takentogether R³ and R⁴ may be a heterocyclic moiety selected from the groupconsisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidino,hexahydroazepinyl, heptamethylenimino, octamethylenimino, morpholino,and 4-lower-alkylpiperazinyl, each of said heterocyclic moieties havingattached as substituents on the carbon atoms 0 to 3 lower alkyl groups,hydroxy or alkoxy, and wherein R² is selected from the group consistingof hydrogen, lower alkyl, lower alkenyl, lower alkoxyalkyl, lowercycloalkyl, lower aryl, lower aralkyl, lower alkaryl, lower alkaralkyl,lower alkoxyaralkyl, and lower haloaralkyl; tautomers thereof andpharmacologically acceptable acid addition salts thereof; and ii. amixture of C₁₂-C₁₅ alkyl lactates; b. a viscosity modifying agentcomprising at least one cellulose or derivative thereof; and c. apharmaceutically acceptable liquid carrier comprising, one or moresolubilizer(s), one or more solubilizing acid(s) or mixtures thereof;wherein the liquid vesicles are suspended within the pharmaceuticallyacceptable liquid carrier.
 2. The composition of claim 1, wherein thesolubilizer comprises one or more C₁-C₃ alcohol(s), one or morepolyhydric alcohol(s) or mixtures thereof.
 3. The composition of claim1, wherein the composition comprises from about 0.1% to about 15% of theminoxidil or a pharmaceutically acceptable salt thereof by weight. 4.The composition of claim 3, wherein the composition comprises from about0.5% to about 10% of the minoxidil or a pharmaceutically acceptable saltthereof by weight.
 5. The composition of claim 1, wherein thepharmaceutically acceptable carrier comprises minoxidil or apharmaceutically acceptable salt thereof.
 6. The composition of claim 1wherein the composition further comprises a polyoxyethylene C₄-C₂₆ fattyether.
 7. The composition of claim 1 wherein the composition furthercomprises a polyoxyethylene C₁₀-C₁₈ fatty ether.
 8. The composition ofclaim 8, wherein the composition comprises from about 0.1% to about 15%,by weight, of the polyoxyethylene C₄-C₂₆ fatty ether.
 9. The compositionof claim 1 wherein the cellulose or derivative thereof is selected frommethyl cellulose or derivatives thereof; hydroxylalkyl cellulosepolymers or derivatives thereof, alkyl hydroxylalkyl cellulose polymersor derivatives thereof; or mixtures thereof.
 10. The composition ofclaim 9 wherein the methyl cellulose or derivatives thereof is selectedfrom methyl cellulose, carboxymethyl cellulose, or mixtures thereof. 11.The composition of claim 9 wherein the hydroxyl alkyl cellulose polymerand derivatives thereof is selected from hydroxymethylcellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose and hydroxybutyl methyl cellulose or mixtures thereof.12. The composition of claim 9 wherein the alkyl hydroxyl alkylcellulose polymers is cetyl hydroxyethyl cellulose.
 13. The compositionof claim 1 wherein the cellulose or derivative thereof ishydroxypropylmethylcellulose.
 14. The composition of claim 9 wherein thecomposition has a viscosity of from about 50 cps to about 30000 cps asmeasure by Brookfield RV at spindle 4, speed 6 RPM.
 15. The compositionof claim 14 wherein the composition has a viscosity of from about 100cps to about 10000cps as measure by Brookfield RV at spindle 4, speed 6RPM.
 16. The composition of claim 9 wherein the composition has a yieldstress value of from about 0.01 Pa·s to about 5 Pa·s as measured using aTA Instruments ARES G2 Rheometer in accordance with the method describedin the specification hereof.
 17. The composition of claim 9 wherein thecomposition has a shear thinning index of 10 or more.
 18. Thecomposition of claim 1 wherein the composition comprises from about 0.1%to about 40% by weight of the one of more C₁-C₃ alcohols.
 19. Thecomposition of claim 18 wherein the one or more C₁-C₃ alcohols comprisesethanol.
 20. The composition of claim 1 wherein the liquid vesicle is anon-phospholipid liquid vesicle.
 21. The composition of claim 1 whereinthe composition is storage stable.